1022688401@GENIA Treebank@formal@@1@S@Molecular regulation of cytokine gene expression during the immune response.@@@@1@11@@oe@16-12-2010 1022688402@GENIA Treebank@formal@@1@S@Cytokine expression by immune system cells plays an important role in the regulation of the immune response.@@@@1@18@@oe@16-12-2010 1022688403@GENIA Treebank@formal@@1@S@On first encounter with antigen, naive CD4+ T helper (Th) cells differentiate into cytokine-producing effector cells.@@@@1@20@@oe@16-12-2010 1022688404@GENIA Treebank@formal@@1@S@Two types of effector cells characterized by their distinct expression of cytokine profiles have been described.@@@@1@17@@oe@16-12-2010 1022688405@GENIA Treebank@formal@@1@S@Th1 cells produce IL-2 and IFN-gamma, whereas Th2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13.@@@@1@22@@oe@16-12-2010 1022688406@GENIA Treebank@formal@@1@S@In many pathological situations, the balance between Th1 and Th2 immune responses determines the outcome of diverse immunologically mediated clinical syndromes including infectious, autoimmune, and allergic diseases.@@@@1@31@@oe@16-12-2010 1022688407@GENIA Treebank@formal@@1@S@However, the molecular basis for the tissue-specific expression of Th1/Th2-like cytokines has remained elusive.@@@@1@16@@oe@16-12-2010 1022688408@GENIA Treebank@formal@@1@S@In this review we evaluate the possible in vivo role of different transcription factors and transcriptional mechanisms in T cell differentiation and the immune response.@@@@1@26@@oe@16-12-2010 1022800801@GENIA Treebank@formal@@1@S@The evolutionarily conserved sequence upstream of the human Ig heavy chain S gamma 3 region is an inducible promoter: synergistic activation by CD40 ligand and IL-4 via cooperative NF-kappa B and STAT-6 binding sites.@@@@1@36@@oe@16-12-2010 1022800802@GENIA Treebank@formal@@1@S@Germline C gamma gene transcription is a crucial event in the process that leads to switch DNA recombination to IgG, but its regulation in the human is poorly understood.@@@@1@31@@oe@16-12-2010 1022800803@GENIA Treebank@formal@@1@S@We took advantage of our monoclonal model of germinal center B cell differentiation, IgM+ IgD+ CL-01 cells, to define the role of the I gamma 3 evolutionarily conserved sequence (ECS) in the germline transcriptional activation of the human C gamma 3 gene.@@@@1@47@@oe@16-12-2010 1022800804@GENIA Treebank@formal@@1@S@The I gamma 3 ECS lies upstream of the major I gamma 3 transcription initiation site and displays more than 90% identity with the corresponding human I gamma 1, I gamma 2, and I gamma 4 regions.@@@@1@41@@oe@16-12-2010 1022800805@GENIA Treebank@formal@@1@S@Reporter luciferase gene vectors containing the human gamma 3 ECS were used to transfect CL-01 cells, which have been shown to undergo Smu-->S gamma 3 DNA recombination, upon engagement of CD40 by CD40 ligand (CD40L) and exposure to IL-4.@@@@1@46@@oe@16-12-2010 1022800806@GENIA Treebank@formal@@1@S@In these transfected CL-01 cells, CD40:CD40L engagement and exposure to IL-4 synergistically induced gamma 3 ECS-dependent luciferase reporter gene activation.@@@@1@22@@oe@16-12-2010 1022800807@GENIA Treebank@formal@@1@S@Targeted mutational analysis demonstrated that a tandem NF-kappa B/Rel binding motif is critical for the gamma 3 ECS responsiveness to both CD40L and IL-4, while a STAT-6-binding site is additionally required for IL-4 inducibility.@@@@1@36@@oe@16-12-2010 1022800808@GENIA Treebank@formal@@1@S@Electrophoretic mobility shift assays showed that p50/p65/c-Rel and STAT-6 are effectively induced by CD40L and IL-4, respectively, and bind to specific DNA motifs within the ECS.@@@@1@29@@oe@16-12-2010 1022800809@GENIA Treebank@formal@@1@S@These partially overlapping CD40L and IL-4 responsive elements are functionally cooperative as the disruption of one of them prevents synergistic promoter activation.@@@@1@23@@oe@16-12-2010 1022800810@GENIA Treebank@formal@@1@S@Thus, the gamma 3 ECS is an inducible promoter containing cis elements that critically mediate CD40L and IL-4-triggered transcriptional activation of the human C gamma 3 gene.@@@@1@29@@oe@16-12-2010 1022801101@GENIA Treebank@formal@@1@S@HLA class I-mediated induction of cell proliferation involves cyclin E-mediated inactivation of Rb function and induction of E2F activity.@@@@1@20@@oe@16-12-2010 1022801102@GENIA Treebank@formal@@1@S@Chronic rejection of transplanted organs is manifested as atherosclerosis of the blood vessels of the allograft.@@@@1@17@@oe@16-12-2010 1022801103@GENIA Treebank@formal@@1@S@HLA class I Ags have been implicated to play a major role in this process, since signaling via HLA class I molecules can induce the proliferation of aortic endothelial as well as smooth muscle cells.@@@@1@37@@oe@16-12-2010 1022801104@GENIA Treebank@formal@@1@S@In this study, we show that HLA class I-mediated induction of cell proliferation correlates with inactivation of the Rb protein in the T cell line Jurkat as well as human aortic endothelial cells.@@@@1@35@@oe@16-12-2010 1022801105@GENIA Treebank@formal@@1@S@HLA class I-mediated inactivation of Rb can be inhibited specifically by neutralizing Abs to basic fibroblast growth factor (bFGF), suggesting a role for FGF receptors in the signaling process.@@@@1@33@@oe@16-12-2010 1022801106@GENIA Treebank@formal@@1@S@Signaling through HLA class I molecules induced cyclin E-associated kinase activity within 4 h in quiescent endothelial cells, and appeared to mediate the inactivation of Rb.@@@@1@28@@oe@16-12-2010 1022801107@GENIA Treebank@formal@@1@S@A cdk2 inhibitor, Olomoucine, as well as a dominant-negative cdk2 construct prevented HLA class I-mediated inactivation of Rb; in contrast, dominant-negative cdk4 and cdk6 constructs had no effect.@@@@1@33@@oe@16-12-2010 1022801108@GENIA Treebank@formal@@1@S@Furthermore, there was no increase in cyclin D-associated kinase activity upon HLA class I ligation, suggesting that cyclin E-dependent kinase activity mediates Rb inactivation, leading to E2F activation and cell proliferation.@@@@1@35@@oe@16-12-2010 1022802601@GENIA Treebank@formal@@1@S@Thrombin-induced p65 homodimer binding to downstream NF-kappa B site of the promoter mediates endothelial ICAM-1 expression and neutrophil adhesion.@@@@1@20@@oe@16-12-2010 1022802602@GENIA Treebank@formal@@1@S@We investigated the mechanisms by which proinflammatory mediator, thrombin, released during intravascular coagulation and tissue injury, induces ICAM-1 (CD54) expression in endothelial cells.@@@@1@29@@oe@16-12-2010 1022802603@GENIA Treebank@formal@@1@S@Stimulation of HUVEC with thrombin resulted in dose- and time-dependent increases in ICAM-1 mRNA and cell surface expression and in ICAM-1-dependent endothelial adhesivity toward polymorphonuclear leukocytes.@@@@1@27@@oe@16-12-2010 1022802604@GENIA Treebank@formal@@1@S@Transient transfection of endothelial cells with ICAM-1 promoter luciferase reporter gene (ICAM-1LUC) constructs indicated that deletion of upstream NF-kappa B site (-533 bases from translation start site) had no effect on thrombin responsiveness, whereas mutation/deletion of downstream NF-kappa B site (-223 bases from the translation start site) prevented the activation of ICAM-1 promoter, indicating that the downstream NF-kappa B site is critical for thrombin inducibility.@@@@1@74@@oe@16-12-2010 1022802605@GENIA Treebank@formal@@1@S@NF-kappa B-directed luciferase activity increased approximately 3-fold when cells transfected with the plasmid pNF-kappa BLUC containing five copies of consensus NF-kappa B site linked to a minimal adenovirus E1B promoter-luciferase gene were exposed to thrombin, indicating that activation of NF-kappa B was essential for thrombin response.@@@@1@48@@oe@16-12-2010 1022802606@GENIA Treebank@formal@@1@S@Gel supershift assays demonstrated that thrombin induced binding of NF-kappa Bp65 (Rel A) to downstream NF-kappa B site of the ICAM-1 promoter.@@@@1@25@@oe@16-12-2010 1022802607@GENIA Treebank@formal@@1@S@Thrombin receptor activation peptide, a 14-amino-acid peptide representing the new NH2 terminus of proteolytically activated receptor-1, mimicked thrombin's action in inducing ICAM-1 expression.@@@@1@27@@oe@16-12-2010 1022802608@GENIA Treebank@formal@@1@S@These data indicate that thrombin activates endothelial ICAM-1 expression and polymorphonuclear leukocyte adhesion by NF-kappa Bp65 binding to the downstream NF-kappa B site of ICAM-1 promoter after proteolytically activated receptor-1 activation.@@@@1@32@@oe@16-12-2010 1022813301@GENIA Treebank@formal@@1@S@Increased glucocorticoid receptor beta in airway cells of glucocorticoid-insensitive asthma.@@@@1@11@@oe@16-12-2010 1022813302@GENIA Treebank@formal@@1@S@Glucocorticoid (GC)-insensitive asthma is a challenging clinical problem that can be associated with life-threatening disease progression.@@@@1@20@@oe@16-12-2010 1022813303@GENIA Treebank@formal@@1@S@The molecular basis of GC insensitivity is unknown.@@@@1@9@@oe@16-12-2010 1022813304@GENIA Treebank@formal@@1@S@Alternative splicing of the GC receptor (GCR) pre-mRNA generates a second GCR, termed GCRbeta, which does not bind GC but antagonizes the transactivating activity of the classic GCR.@@@@1@33@@oe@16-12-2010 1022813305@GENIA Treebank@formal@@1@S@Thus increased expression of GCRbeta could account for glucocorticoid insensitivity.@@@@1@11@@oe@16-12-2010 1022813306@GENIA Treebank@formal@@1@S@Bronchoalveolar lavage (BAL) cells and peripheral blood mononuclear cells (PBMC) were examined for GCRbeta immunoreactivity using a GCRbeta-specific antibody by immunohistochemical staining.@@@@1@27@@oe@16-12-2010 1022813307@GENIA Treebank@formal@@1@S@Cell localization of GCRbeta expression was performed using a double immunostaining technique.@@@@1@13@@oe@16-12-2010 1022813308@GENIA Treebank@formal@@1@S@Patients with GC-insensitive asthma expressed a significantly higher number of GCRbeta-immunoreactive cells in their BAL and peripheral blood than GC-sensitive asthmatics or normal control subjects.@@@@1@26@@oe@16-12-2010 1022813309@GENIA Treebank@formal@@1@S@Furthermore, GCRbeta expression in GC-insensitive asthma was particularly high in airway T cells, which are thought to play a major role in the pathogenesis of asthma.@@@@1@29@@oe@16-12-2010 1022813310@GENIA Treebank@formal@@1@S@We also examined the expression of GCRbeta in specimens from the airways of patients with chronic bronchitis.@@@@1@18@@oe@16-12-2010 1022813311@GENIA Treebank@formal@@1@S@In chronic bronchitis, few cells were GCRbeta-positive and their numbers did not differ significantly from normal control subjects.@@@@1@20@@oe@16-12-2010 1022813312@GENIA Treebank@formal@@1@S@We conclude that GC-insensitive asthma is associated with increased expression of GCRbeta in airway T cells.@@@@1@17@@oe@16-12-2010 1022923101@GENIA Treebank@formal@@1@S@Regulation of Fas ligand expression and cell death by apoptosis-linked gene 4.@@@@1@13@@oe@16-12-2010 1022923102@GENIA Treebank@formal@@1@S@Programmed cell death is a process required for the normal development of an organism.@@@@1@15@@oe@16-12-2010 1022923103@GENIA Treebank@formal@@1@S@One of the best understood apoptotic pathways occurs in T lymphocytes and is mediated by Fas/Fas ligand (FasL) interaction.@@@@1@22@@oe@16-12-2010 1022923104@GENIA Treebank@formal@@1@S@During studies of apoptosis induced by T cell-receptor engagement, we identified ALG-4F, a truncated transcript that prevents T cell-receptor-induced FasL upregulation and cell death.@@@@1@27@@oe@16-12-2010 1022923105@GENIA Treebank@formal@@1@S@Overexpression of full-length ALG-4 induced transcription of FasL and, consequently, apoptosis.@@@@1@14@@oe@16-12-2010 1022923106@GENIA Treebank@formal@@1@S@These results indicate that ALG-4 is necessary and sufficient for FasL expression.@@@@1@13@@oe@16-12-2010 1022923107@GENIA Treebank@formal@@1@S@Fas/FasL interaction initiates cell death in many other systems, and its dysregulation is a mechanism by which several pathologic conditions arise.@@@@1@23@@oe@16-12-2010 1022923108@GENIA Treebank@formal@@1@S@Understanding the molecular mechanisms of FasL regulation could be very useful in elucidating how these diseases develop and in identifying potential therapeutic targets.@@@@1@24@@oe@16-12-2010 1022927501@GENIA Treebank@formal@@1@S@High molecular weight dextran sulfate increases the activity of NF-kappaB-regulated promoter in monocyte-derived macrophages.@@@@1@15@@oe@16-12-2010 1022927502@GENIA Treebank@formal@@1@S@It is known that sulfated polysaccharides can mimic the action of common T-cell mitogens.@@@@1@15@@oe@16-12-2010 1022927503@GENIA Treebank@formal@@1@S@To investigate the molecular basis of the mitogenic effect of high molecular weight dextran sulfate (HMDS), monocyte-derived macrophages were transfected with recombinant plasmid containing chloramphenicol acetyl transferase (CAT) reporter gene under the control of the HIV-1 long terminal repeat (LTR) promoter, which is regulated by transcription factor NF-kappaB.@@@@1@57@@oe@16-12-2010 1022927504@GENIA Treebank@formal@@1@S@We observed that HMDS, similar to bacterial lipopolysaccharide (LPS), increases the expression of CAT reporter gene suggesting increased activity of NF-kappaB.@@@@1@26@@oe@16-12-2010 1022927505@GENIA Treebank@formal@@1@S@The activation of NF-kappaB correlated with the increased expression of B7.1 molecules.@@@@1@13@@oe@16-12-2010 1022927506@GENIA Treebank@formal@@1@S@It was postulated that this NF-kappaB-regulated promoter might play a role in the activation of the accessory cells as well as the rate of replication of HIV-1 in monocyte-derived macrophages.@@@@1@31@@oe@16-12-2010 1022932401@GENIA Treebank@formal@@1@S@Differences in phosphorylation of the IL-2R associated JAK/STAT proteins between HTLV-I(+), IL-2-independent and IL-2-dependent cell lines and uncultured leukemic cells from patients with adult T-cell lymphoma/leukemia.@@@@1@28@@oe@16-12-2010 1022932402@GENIA Treebank@formal@@1@S@To determine activation status of the IL-2R-associated (Jak/STAT) pathway in the HTLV-I infected cells, we examined tyrosine phosphorylation of Jak3, STAT3, and STAT5 in several HTLV-I(+) T-cell lines and in uncultured leukemic T cells isolated from patients with adult T-cell lymphoma/leukemia (ATLL).@@@@1@50@@oe@16-12-2010 1022932403@GENIA Treebank@formal@@1@S@Constitutive basal phosphorylation of Jak3 and, usually, STAT3 and STAT5 was detected in all four IL-2-independent cell lines tested, but in none of the three IL-2-dependent cell lines.@@@@1@32@@oe@16-12-2010 1022932404@GENIA Treebank@formal@@1@S@Similarly, there was no detectable basal phosphorylation of Jak3 and STAT5 in the leukemic cells from ATLL patients (0/8 and 0/3, respectively).@@@@1@27@@oe@16-12-2010 1022932405@GENIA Treebank@formal@@1@S@However, stimulation with IL-2 resulted in Jak3 and STAT5 phosphorylation in both leukemic ATLL cells and IL-2-dependent lines.@@@@1@20@@oe@16-12-2010 1022932406@GENIA Treebank@formal@@1@S@Furthermore, expression of SHP-1 phosphatase which is a negative regulator of cytokine receptor signaling, was lost in most IL-2 independent cell lines (3/4) but not in the leukemic ATLL cells (0/3).@@@@1@38@@oe@16-12-2010 1022932407@GENIA Treebank@formal@@1@S@Finally, the HTLV-I(+) T-cell lines (313) but not the control, HTLV-I(-) T-cell lines were resistant to rapamycin and its novel analog RAD.@@@@1@27@@oe@16-12-2010 1022932408@GENIA Treebank@formal@@1@S@We conclude that (1) HTLV-I infection per se does not result in a constitutive phosphorylation of the Jak3, STAT3, and STAT5 proteins; (2) malignant transformation in at least some cases of ATLL does not require the constitutive, but may require IL-2-induced, activation of the IL-2R Jak/STAT pathway; and (3) there are major differences in T-cell immortalization mechanism(s) which appear to involve SHP-1 and target molecules for rapamycin and RAD.@@@@1@85@@oe@16-12-2010 1022981501@GENIA Treebank@formal@@1@S@CTLA-4-Mediated inhibition of early events of T cell proliferation.@@@@1@10@@oe@16-12-2010 1022981502@GENIA Treebank@formal@@1@S@CTLA-4 engagement by mAbs inhibits, while CD28 enhances, IL-2 production and proliferation upon T cell activation.@@@@1@19@@oe@16-12-2010 1022981503@GENIA Treebank@formal@@1@S@Here, we have analyzed the mechanisms involved in CTLA-4-mediated inhibition of T cell activation of naive CD4+ T cells using Ab cross-linking.@@@@1@24@@oe@16-12-2010 1022981504@GENIA Treebank@formal@@1@S@CTLA-4 ligation inhibited CD3/CD28-induced IL-2 mRNA accumulation by inhibiting IL-2 transcription, which appears to be mediated in part through decreasing NF-AT accumulation in the nuclei.@@@@1@27@@oe@16-12-2010 1022981505@GENIA Treebank@formal@@1@S@However, CTLA-4 ligation did not appear to affect the CD28-mediated stabilization of IL-2 mRNA.@@@@1@16@@oe@16-12-2010 1022981506@GENIA Treebank@formal@@1@S@Further, CTLA-4 engagement inhibited progression through the cell cycle by inhibiting the production of cyclin D3, cyclin-dependent kinase (cdk)4, and cdk6 when the T cells were stimulated with anti-CD3/CD28 and with anti-CD3 alone.@@@@1@40@@oe@16-12-2010 1022981507@GENIA Treebank@formal@@1@S@These results indicate that CTLA-4 signaling inhibits events early in T cell activation both at IL-2 transcription and at the level of IL-2-independent events of the cell cycle, and does not simply oppose CD28-mediated costimulation.@@@@1@37@@oe@16-12-2010 1022982001@GENIA Treebank@formal@@1@S@Fibroblast growth factor-1 (FGF-1) enhances IL-2 production and nuclear translocation of NF-kappaB in FGF receptor-bearing Jurkat T cells.@@@@1@21@@oe@16-12-2010 1022982002@GENIA Treebank@formal@@1@S@Fibroblast growth factors (FGFs) are heparin-binding proteins crucial to embryogenesis, angiogenesis, and wound healing.@@@@1@19@@oe@16-12-2010 1022982003@GENIA Treebank@formal@@1@S@FGF-1 is abundantly expressed in the synovium in rheumatoid arthritis and in rejecting allografts, sites of chronic immune-mediated inflammation.@@@@1@21@@oe@16-12-2010 1022982004@GENIA Treebank@formal@@1@S@The frequency of FGF-1-responsive T cells is increased in the peripheral blood of these disorders, and a high percentage of infiltrating T cells in rheumatoid arthritis synovium express receptors for FGF-1.@@@@1@33@@oe@16-12-2010 1022982005@GENIA Treebank@formal@@1@S@To understand the action of FGF-1 in T cells, studies were initiated in Jurkat T cells that express the signaling isoform of FGF receptor-1.@@@@1@26@@oe@16-12-2010 1022982006@GENIA Treebank@formal@@1@S@These experiments show that FGF-1 stimulation of Jurkat T cells provides a second signal that augments TCR-mediated IL-2 production.@@@@1@20@@oe@16-12-2010 1022982007@GENIA Treebank@formal@@1@S@Analogous to costimulation via CD28, this activity is mediated through activation of Rel/kappaB, a family of transcription factors known to regulate IL-2 and other activation-inducible proteins.@@@@1@29@@oe@16-12-2010 1022982008@GENIA Treebank@formal@@1@S@FGF-1 alone induces modest nuclear translocation of kappaB-binding proteins, and this translocation is enhanced by the combination of anti-CD3 and FGF-1.@@@@1@23@@oe@16-12-2010 1022982009@GENIA Treebank@formal@@1@S@This NF-kappaB binding complex is composed of transcriptionally active p65(RelA)/p50 heterodimers and results primarily from the targeted degradation of IkappaB-alpha, an inhibitor that sequesters Rel/kappaB in the cytoplasm.@@@@1@34@@oe@16-12-2010 1022982010@GENIA Treebank@formal@@1@S@These data are the first to show a connection between FGF-1 signaling and NF-kappaB activation outside of embryonic development.@@@@1@20@@oe@16-12-2010 1022982011@GENIA Treebank@formal@@1@S@The signaling events that link FGF receptor-1 engagement and NF-kappaB activation in Jurkat are probably distinct from the CD28 costimulation pathway, since FGF-1-induced Rel/kappaB binding proteins do not contain significant levels of c-Rel and are not identical with the CD28 response complex.@@@@1@44@@oe@16-12-2010 1022983701@GENIA Treebank@formal@@1@S@USF/c-Myc enhances, while Yin-Yang 1 suppresses, the promoter activity of CXCR4, a coreceptor for HIV-1 entry.@@@@1@20@@oe@16-12-2010 1022983702@GENIA Treebank@formal@@1@S@Transcription factors USF1 and USF2 up-regulate gene expression (i.e., HIV-1 long terminal repeats) via interaction with an E box on their target promoters, which is also a binding site for c-Myc.@@@@1@36@@oe@16-12-2010 1022983703@GENIA Treebank@formal@@1@S@The c-Myc oncoprotein is important in control of cellular proliferation and differentiation, while Yin-Yang 1 (YY1) has been shown to control the expression of a number of cellular and viral genes.@@@@1@35@@oe@16-12-2010 1022983704@GENIA Treebank@formal@@1@S@These two proteins physically interact with each other and mutually inhibit their respective biological functions.@@@@1@16@@oe@16-12-2010 1022983705@GENIA Treebank@formal@@1@S@In this study, we show that USF/c-Myc up-regulates, while YY1 down-regulates the promoter activity of CXCR4, a coreceptor for T cell-tropic HIV-1 entry.@@@@1@27@@oe@16-12-2010 1022983706@GENIA Treebank@formal@@1@S@We have identified an E box around -260 and a YY1 binding site around -300 relative to the transcription start site.@@@@1@22@@oe@16-12-2010 1022983707@GENIA Treebank@formal@@1@S@Mutation of the E box abolished USF/c-Myc- mediated up-regulation of CXCR4 promoter activity, and mutation of the YY1 binding site was associated with unresponsiveness to YY1-mediated inhibition.@@@@1@28@@oe@16-12-2010 1022983708@GENIA Treebank@formal@@1@S@These data suggest that USF/c-Myc and YY1 may play an important role in the HIV-1-replicative cycle, by modulating both the viral fusion/entry process and viral expression.@@@@1@28@@oe@16-12-2010 1022984101@GENIA Treebank@formal@@1@S@Signaling through the lymphotoxin-beta receptor stimulates HIV-1 replication alone and in cooperation with soluble or membrane-bound TNF-alpha.@@@@1@18@@oe@16-12-2010 1022984102@GENIA Treebank@formal@@1@S@The level of ongoing HIV-1 replication within an individual is critical to HIV-1 pathogenesis.@@@@1@15@@oe@16-12-2010 1022984103@GENIA Treebank@formal@@1@S@Among host immune factors, the cytokine TNF-alpha has previously been shown to increase HIV-1 replication in various monocyte and T cell model systems.@@@@1@25@@oe@16-12-2010 1022984104@GENIA Treebank@formal@@1@S@Here, we demonstrate that signaling through the TNF receptor family member, the lymphotoxin-beta (LT-beta) receptor (LT-betaR), also regulates HIV-1 replication.@@@@1@28@@oe@16-12-2010 1022984105@GENIA Treebank@formal@@1@S@Furthermore, HIV-1 replication is cooperatively stimulated when the distinct LT-betaR and TNF receptor systems are simultaneously engaged by their specific ligands.@@@@1@23@@oe@16-12-2010 1022984106@GENIA Treebank@formal@@1@S@Moreover, in a physiological coculture cellular assay system, we show that membrane-bound TNF-alpha and LT-alpha1beta2 act virtually identically to their soluble forms in the regulation of HIV-1 replication.@@@@1@31@@oe@16-12-2010 1022984107@GENIA Treebank@formal@@1@S@Thus, cosignaling via the LT-beta and TNF-alpha receptors is probably involved in the modulation of HIV-1 replication and the subsequent determination of HIV-1 viral burden in monocytes.@@@@1@29@@oe@16-12-2010 1022984108@GENIA Treebank@formal@@1@S@Intriguingly, surface expression of LT-alpha1beta2 is up-regulated on a T cell line acutely infected with HIV-1, suggesting a positive feedback loop between HIV-1 infection, LT-alpha1beta2 expression, and HIV-1 replication.@@@@1@35@@oe@16-12-2010 1022984109@GENIA Treebank@formal@@1@S@Given the critical role that LT-alpha1beta2 plays in lymphoid architecture, we speculate that LT-alpha1beta2 may be involved in HIV-associated abnormalities of the lymphoid organs.@@@@1@26@@oe@16-12-2010 1023134501@GENIA Treebank@formal@@1@S@Glucocorticoid receptors are down-regulated in inflamed colonic mucosa but not in peripheral blood mononuclear cells from patients with inflammatory bowel disease [see comments]@@@@1@25@@oe@16-12-2010 1023134502@GENIA Treebank@formal@@1@S@BACKGROUND: Growing evidence indicates that the immune system and the hypothalamic-pituitary-adrenal system are linked by several mechanisms, for example intracellular glucocorticoid receptors (hGR).@@@@1@28@@oe@16-12-2010 1023134503@GENIA Treebank@formal@@1@S@Glucocorticoids are the standard treatment of acute attacks of inflammatory bowel disease (IBD).@@@@1@16@@oe@16-12-2010 1023134504@GENIA Treebank@formal@@1@S@Binding of glucocorticoids to hGR down-regulates the transcription of inflammatory genes that can propagate IBD.@@@@1@16@@oe@16-12-2010 1023134505@GENIA Treebank@formal@@1@S@PATIENTS AND METHODS: IBD patients were either treated with 5-60 mg of prednisolone for more than 1 week or were without glucocorticoid treatment for more than 4 weeks.@@@@1@30@@oe@16-12-2010 1023134506@GENIA Treebank@formal@@1@S@hGR levels were determined from isolated cytosol of peripheral blood mononuclear cells (PBMCs) or mucosal biopsies using a radioassay with [3H]-dexamethasone.@@@@1@24@@oe@16-12-2010 1023134507@GENIA Treebank@formal@@1@S@Interleukin (IL) 6 levels were determined by enzyme-linked immunosorbent assay (ELISA).@@@@1@16@@oe@16-12-2010 1023134508@GENIA Treebank@formal@@1@S@RESULTS: The systemic (PBMC) hGR levels of corticosteroid-treated IBD patients were significantly lower than those of control subjects (59.6 +/- 57.1 dpm mg-1 cytosol protein vs. 227.0 +/- 90.8 dpm mg-1 cytosol protein, P = 0.007) and IBD patients not receiving glucocorticoid treatment (179.7 +/- 171.3 dpm mg-1 cytosol protein, P = 0.002).@@@@1@63@@oe@16-12-2010 1023134509@GENIA Treebank@formal@@1@S@Systemic hGR levels in untreated IBD patients did not differ significantly from those in control subjects.@@@@1@17@@oe@16-12-2010 1023134510@GENIA Treebank@formal@@1@S@In patients with connective tissue diseases, systemic hGR levels were also found to be decreased in the absence of glucocorticoid treatment.@@@@1@23@@oe@16-12-2010 1023134511@GENIA Treebank@formal@@1@S@Systemic hGR levels in patients with Crohn's disease (CD) treated with steroids (66.6 +/- 61.0 dpm mg-1 cytosol protein) were not different from those in patients with ulcerative colitis (UC) (56.1 +/- 51.6 dpm mg-1 cytosol protein).@@@@1@47@@oe@16-12-2010 1023134512@GENIA Treebank@formal@@1@S@In contrast to these findings, mucosal hGR levels were significantly decreased in both steroid-treated (18.0 +/- 15.5) and not steroid-treated (37.8 +/- 30.5) patients compared with control subjects ( 125.6 +/- 97.1; P = 0.00009 and P = 0.0008 respectively ).@@@@1@48@@oe@16-12-2010 1023134513@GENIA Treebank@formal@@1@S@IL-6 levels in all IBD groups with and without steroids were significantly different from those in control subjects.@@@@1@19@@oe@16-12-2010 1023134514@GENIA Treebank@formal@@1@S@CONCLUSION: In IBD there is no difference in systemic hGR levels between not steroid-treated patients and control subjects, in spite of inflammatory activity (IL-6).@@@@1@29@@oe@16-12-2010 1023134515@GENIA Treebank@formal@@1@S@Mucosal hGR levels were decreased independently of treatment, probably leading to a decreased protection against NF-kappaB action in the intestinal mucosa.@@@@1@23@@oe@16-12-2010 1023238501@GENIA Treebank@formal@@1@S@Resistance to tumor necrosis factor induced apoptosis in vitro correlates with high metastatic capacity of cells in vivo.@@@@1@19@@oe@16-12-2010 1023238502@GENIA Treebank@formal@@1@S@TNF is one of the cytokines secreted by the cells of the immune system.@@@@1@15@@oe@16-12-2010 1023238503@GENIA Treebank@formal@@1@S@Our data demonstrate that those cell lines lacking capability to form metastatic tumors in vivo are susceptible to TNF induced apoptosis in vitro.@@@@1@24@@oe@16-12-2010 1023238504@GENIA Treebank@formal@@1@S@However, cell lines with high metastatic potential are resistant to TNF in vitro.@@@@1@15@@oe@16-12-2010 1023238505@GENIA Treebank@formal@@1@S@Furthermore, the same cell lines were resistant to cytolytic action of other cytotoxic proteins secreted by LAK cells.@@@@1@20@@oe@16-12-2010 1023238506@GENIA Treebank@formal@@1@S@Our data showed that TNF resistance in vitro correlates with the increased level of transcription factor NF-kappaB.@@@@1@18@@oe@16-12-2010 1023238507@GENIA Treebank@formal@@1@S@This finding may provide a tool to improve current protocols of immunotherapy and insights to how tumor cells are or are not killed by LAK cells.@@@@1@27@@oe@16-12-2010 1023387501@GENIA Treebank@formal@@1@S@NF-kappaB activation is required for C5a-induced interleukin-8 gene expression in mononuclear cells.@@@@1@13@@oe@16-12-2010 1023387502@GENIA Treebank@formal@@1@S@C5a, a potent peptide chemoattractant, stimulates interleukin-8 (IL-8) secretion from peripheral blood mononuclear cells (PBMC).@@@@1@22@@oe@16-12-2010 1023387503@GENIA Treebank@formal@@1@S@Experiments were conducted to understand the mechanisms for C5a-induced IL-8 production, which was 14-fold greater than that in unstimulated cells by 2 hours.@@@@1@25@@oe@16-12-2010 1023387504@GENIA Treebank@formal@@1@S@IL-8 secretion was accompanied by accumulation of IL-8 mRNA in the cytosol and by nuclear expression of a kappaB DNA binding activity within 30 minutes.@@@@1@26@@oe@16-12-2010 1023387505@GENIA Treebank@formal@@1@S@AP-1 but not NF-IL-6 DNA binding activity was also detected in C5a-stimulated PBMC; however, its delayed expression (maximal at 4 hours) suggested a less important role in the rapid production of IL-8.@@@@1@37@@oe@16-12-2010 1023387506@GENIA Treebank@formal@@1@S@The correlation between C5a-induced kappaB binding activity and IL-8 gene expression was examined in the RAW264.7 macrophage cells using reporter genes directed by the kappaB sequence from IkappaBalpha and IL-8 promoter regions.@@@@1@33@@oe@16-12-2010 1023387507@GENIA Treebank@formal@@1@S@C5a-induced reporter gene expression was abolished by introducing mutations into the kappaB sites and by coexpression of a dominant negative IkappaBalpha construct resistant to agonist-induced phosphorylation.@@@@1@27@@oe@16-12-2010 1023387508@GENIA Treebank@formal@@1@S@Pertussis toxin, which ADP-ribosylates the Gi proteins known to couple to the C5a receptor, produced minimal inhibition of C5a-induced IL-8 expression and had little effect on C5a-induced calcium mobilization in RAW264.7 cells.@@@@1@35@@oe@16-12-2010 1023387509@GENIA Treebank@formal@@1@S@These results suggest that NF-kappaB activation is required for C5a-induced IL-8 gene expression and that this response is mediated primarily through a pertussis toxin-insensitive pathway.@@@@1@26@@oe@16-12-2010 1023387901@GENIA Treebank@formal@@1@S@Transcriptional targeting of retroviral vectors to the erythroblastic progeny of transduced hematopoietic stem cells.@@@@1@15@@oe@16-12-2010 1023387902@GENIA Treebank@formal@@1@S@Targeted expression to specific tissues or cell lineages is a necessary feature of a gene therapy vector for many clinical applications, such as correction of hemoglobinopathies or thalassemias by transplantation of genetically modified hematopoietic stem cells.@@@@1@38@@oe@16-12-2010 1023387903@GENIA Treebank@formal@@1@S@We developed retroviral vectors in which the constitutive viral enhancer in the U3 region of the 3' LTR is replaced by an autoregulatory enhancer of the erythroid-specific GATA-1 transcription factor gene.@@@@1@32@@oe@16-12-2010 1023387904@GENIA Treebank@formal@@1@S@The replaced enhancer is propagated to the 5' LTR upon integration into the target cell genome.@@@@1@17@@oe@16-12-2010 1023387905@GENIA Treebank@formal@@1@S@The modified vectors were used to transduce human hematopoietic cell lines, cord blood-derived CD34(+) stem/progenitor cells, and murine bone marrow repopulating stem cells.@@@@1@26@@oe@16-12-2010 1023387906@GENIA Treebank@formal@@1@S@The expression of appropriate reporter genes (triangle upLNGFR, EGFP) was analyzed in the differentiated progeny of transduced stem cells in vitro, in liquid culture as well as in clonogenic assay, and in vivo, after bone marrow transplantation in lethally irradiated mice.@@@@1@48@@oe@16-12-2010 1023387907@GENIA Treebank@formal@@1@S@The GATA-1 autoregulatory enhancer effectively restricts the expression of the LTR-driven proviral transcription unit to the erythroblastic progeny of both human progenitors and mouse-repopulating stem cells.@@@@1@27@@oe@16-12-2010 1023387908@GENIA Treebank@formal@@1@S@Packaging of viral particles, integration into the target genome, and stability of the integrated provirus are not affected by the LTR modification.@@@@1@25@@oe@16-12-2010 1023387909@GENIA Treebank@formal@@1@S@Enhancer replacement is therefore an effective strategy to target expression of a retroviral transgene to a specific progeny of transduced hematopoietic stem cells.@@@@1@24@@oe@16-12-2010 1023388201@GENIA Treebank@formal@@1@S@An essential role for NF-kappaB in human CD34(+) bone marrow cell survival.@@@@1@13@@oe@16-12-2010 1023388202@GENIA Treebank@formal@@1@S@The transcription factor, NF-kappaB, is important for T-cell activation, B-cell maturation, and human immunodeficiency virus transcription and plays a role in alternatively mediating and protecting against apoptosis in a variety of cell types.@@@@1@38@@oe@16-12-2010 1023388203@GENIA Treebank@formal@@1@S@However, a role for NF-kappaB in human CD34(+) bone marrow cells has not been described.@@@@1@17@@oe@16-12-2010 1023388204@GENIA Treebank@formal@@1@S@We provide evidence here that virtually all human CD34(+) bone marrow cells express NF-kappaB that can be activated by exposure to phorbol 12-myristate 13-acetate and a variety of cytokines, eg, tumor necrosis factor alpha, interleukin-3, and granulocyte-macrophage colony-stimulating factor.@@@@1@44@@oe@16-12-2010 1023388205@GENIA Treebank@formal@@1@S@In addition, we demonstrate that NF-kappaB may be required for human CD34(+) bone marrow cell clonogenic function and survival.@@@@1@21@@oe@16-12-2010 1023388206@GENIA Treebank@formal@@1@S@These results offer insight into a new role for NF-kappaB in maintaining survival and function in hematopoietic stem and progenitor cells and suggest that proposed strategies involving inhibition of NF-kappaB activation as an adjunct to cancer chemotherapy should be approached with caution.@@@@1@43@@oe@16-12-2010 1023388801@GENIA Treebank@formal@@1@S@Unicellular-unilineage erythropoietic cultures: molecular analysis of regulatory gene expression at sibling cell level.@@@@1@15@@oe@16-12-2010 1023388802@GENIA Treebank@formal@@1@S@In vitro studies on hematopoietic control mechanisms have been hampered by the heterogeneity of the analyzed cell populations, ie, lack of lineage specificity and developmental stage homogeneity of progenitor/precursor cells growing in culture.@@@@1@36@@oe@16-12-2010 1023388803@GENIA Treebank@formal@@1@S@We developed unicellular culture systems for unilineage differentiation of purified hematopoietic progenitor cells followed by daughter cell analysis at cellular and molecular level.@@@@1@24@@oe@16-12-2010 1023388804@GENIA Treebank@formal@@1@S@In the culture system reported here, (1) the growth factor (GF) stimulus induces cord blood (CB) progenitor cells to proliferate and differentiate/mature exclusively along the erythroid lineage; (2) this erythropoietic wave is characterized by less than 4% apoptotic cells; (3) asymmetric divisions are virtually absent, ie, nonresponsive hematopoietic progenitors with no erythropoietic potential are forced into apoptosis; (4) the system is cell division controlled (cdc), ie, the number of divisions performed by each cell is monitored.@@@@1@100@@oe@16-12-2010 1023388805@GENIA Treebank@formal@@1@S@Single-cell reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was applied to this culture system to investigate gene expression of diverse receptors, markers of differentiation, and transcription factors (EKLF, GATA-1, GATA-2, p45 NF-E2, PU.1, and SCL/Tal1) at discrete stages of erythropoietic development.@@@@1@52@@oe@16-12-2010 1023388806@GENIA Treebank@formal@@1@S@Freshly isolated CD34(+) cells expressed CD34, c-kit, PU.1, and GATA-2 but did not express CD36, erythropoietin receptor (EpoR), SCL/Tal1, EKLF, NF-E2, GATA-1, or glyocophorin A (GPA).@@@@1@40@@oe@16-12-2010 1023388807@GENIA Treebank@formal@@1@S@In early to intermediate stages of erythroid differentiation we monitored the induction of CD36, Tal1, EKLF, NF-E2, and GATA-1 that preceeded expression of EpoR.@@@@1@29@@oe@16-12-2010 1023388808@GENIA Treebank@formal@@1@S@In late stages of erythroid maturation, GPA was upregulated, whereas CD34, c-kit, PU.1, and GATA-2 were barely or not detected.@@@@1@26@@oe@16-12-2010 1023388809@GENIA Treebank@formal@@1@S@In addition, competitive single-cell RT-PCR was used to assay CD34 mRNA transcripts in sibling CD34(+) CD38(-) cells differentiating in unilineage erythroid cultures: this analysis allowed us to semiquantitate the gradual downmodulation of CD34 mRNA from progenitor cells through their differentiating erythroid progeny.@@@@1@45@@oe@16-12-2010 1023388810@GENIA Treebank@formal@@1@S@It is concluded that this novel culture system, coupled with single-cell RT-PCR analysis, may eliminate the ambiguities intrinsic to molecular studies on heterogeneous populations of hematopoietic progenitors/precursors growing in culture, particularly in the initial stages of development.@@@@1@41@@oe@16-12-2010 1023392701@GENIA Treebank@formal@@1@S@Control of cell cycle entry and apoptosis in B lymphocytes infected by Epstein-Barr virus.@@@@1@15@@oe@16-12-2010 1023392702@GENIA Treebank@formal@@1@S@Infection of human B cells with Epstein-Barr virus (EBV) results in activation of the cell cycle and cell growth.@@@@1@22@@oe@16-12-2010 1023392703@GENIA Treebank@formal@@1@S@To interpret the mechanisms by which EBV activates the cell, we have assayed many proteins involved in control of the G0 and G1 phases of the cell cycle and regulation of apoptosis.@@@@1@34@@oe@16-12-2010 1023392704@GENIA Treebank@formal@@1@S@In EBV infection most of the changes, including the early induction of cyclin D2, are dependent on expression of EBV genes, but an alteration in the E2F-4 profile was partly independent of viral gene expression, presumably occurring in response to signal transduction activated when the virus binds to its receptor, CD21.@@@@1@57@@oe@16-12-2010 1023392705@GENIA Treebank@formal@@1@S@By comparing the expression of genes controlling apoptosis, including those encoding several members of the BCL-2 family of proteins, the known relative resistance of EBV-immortalized B-cell lines to apoptosis induced by low serum was found to correlate with expression of both BCL-2 and A20.@@@@1@47@@oe@16-12-2010 1023392706@GENIA Treebank@formal@@1@S@A20 can be regulated by the NF-kappaB transcription factor, which is known to be activated by the EBV LMP-1 protein.@@@@1@22@@oe@16-12-2010 1023392707@GENIA Treebank@formal@@1@S@Quantitative assays demonstrated a direct temporal relationship between LMP-1 protein levels and active NF-kappaB during the time course of infection.@@@@1@21@@oe@16-12-2010 1023394701@GENIA Treebank@formal@@1@S@Immortalization of CD4(+) and CD8(+) T lymphocytes by human T-cell leukemia virus type 1 Tax mutants expressed in a functional molecular clone.@@@@1@23@@oe@16-12-2010 1023394702@GENIA Treebank@formal@@1@S@The human T-cell leukemia virus type 1 (HTLV-1) transcriptional trans-activator Tax has been demonstrated to have transforming activity in multiple cell culture and transgenic-mouse models.@@@@1@28@@oe@16-12-2010 1023394703@GENIA Treebank@formal@@1@S@In addition to activating transcription from the viral long terminal repeat (LTR) through the cyclic AMP response element binding protein/activating transcription factor (CREB/ATF) family of transcription factors, Tax activates the expression of multiple cellular promoters through the NF-kappaB pathway of transcriptional activation.@@@@1@48@@oe@16-12-2010 1023394704@GENIA Treebank@formal@@1@S@The Tax mutants M22 and M47 have previously been demonstrated to selectively abrogate the ability of Tax to activate transcription through the NF-kappaB or CREB/ATF pathway, respectively.@@@@1@29@@oe@16-12-2010 1023394705@GENIA Treebank@formal@@1@S@These mutations were introduced in the tax gene of the ACH functional molecular clone of HTLV-1, and virus produced from the mutant ACH clones was examined for the ability to replicate and immortalize primary human lymphocytes.@@@@1@38@@oe@16-12-2010 1023394706@GENIA Treebank@formal@@1@S@While virus derived from the clone containing the M47 mutation retained the ability to immortalize T lymphocytes, the M22 mutant lost the ability to immortalize infected cells.@@@@1@29@@oe@16-12-2010 1023394707@GENIA Treebank@formal@@1@S@These results indicate that activation of the CREB/ATF pathway by Tax is dispensable for the immortalization of T cells by HTLV-1, whereas activation of the NF-kappaB pathway may be critical.@@@@1@32@@oe@16-12-2010 1023547601@GENIA Treebank@formal@@1@S@The oestrogen receptor codon 10 polymorphism detected in breast cancer is also present in non-malignant cells.@@@@1@17@@oe@16-12-2010 1023547602@GENIA Treebank@formal@@1@S@The effect of oestrogens on oestrogen-receptive organs and cells is mediated via intracellular receptors (ERalpha and ERbeta).@@@@1@20@@oe@16-12-2010 1023547603@GENIA Treebank@formal@@1@S@Oestrogen receptor gene polymorphisms in the region encoding the N-terminal portion of the protein are reportedly associated with pathological conditions including breast cancer, hypertension, spontaneous abortion and coronary heart disease.@@@@1@33@@oe@16-12-2010 1023547604@GENIA Treebank@formal@@1@S@A silent mutation in codon 10 of exon 1, detected in ER-negative and ER-positive human breast cancer cell lines, in breast tumors and blood DNA from breast cancer patients, has been recognized as a polymorphic site.@@@@1@40@@oe@16-12-2010 1023547605@GENIA Treebank@formal@@1@S@In this study we examined, by denaturing gradient-gel electrophoresis and DNA sequence analysis, the possible presence of a codon 10 polymorphic site in normal oestrogen target organs and cells such as the uterus (myometrium and endometrium), in the placenta and peripheral blood mononuclear cells and in a benign uterus tumour (leiomyoma).@@@@1@59@@oe@16-12-2010 1023547606@GENIA Treebank@formal@@1@S@We have detected ER codon 10 polymorphism in these samples and have compared them to those observed in breast cancer samples.@@@@1@22@@oe@16-12-2010 1023547607@GENIA Treebank@formal@@1@S@All tissues and cells studied were homozygous for the wild-type gene, and were heterozygous as well as homozygous for the codon-10-variant type.@@@@1@24@@oe@16-12-2010 1023547608@GENIA Treebank@formal@@1@S@These results indicate that the presence of the codon-10-variant type is not a characteristic of breast cancer.@@@@1@18@@oe@16-12-2010 1023547609@GENIA Treebank@formal@@1@S@Out current findings suggest that further investigations are warranted to elucidate the possible linkage of ER codon 10 polymorphism to physiological and pathological conditions.@@@@1@25@@oe@16-12-2010 1023550901@GENIA Treebank@formal@@1@S@HIV-1 reactivation in resting peripheral blood mononuclear cells of infected adults upon in vitro CD4 cross-linking by ligands of the CDR2-loop in extracellular domain 1.@@@@1@26@@oe@16-12-2010 1023550902@GENIA Treebank@formal@@1@S@HIV-1 infects resting peripheral blood mononuclear cells (PBMCs) but remains inactive state until subsequent cell activation.@@@@1@19@@oe@16-12-2010 1023550903@GENIA Treebank@formal@@1@S@We have demonstrated that the cross-linking of cell surface CD4 by gp120-anti-gp120 immune complexes or heat-inactivated HIV-1 (iHIV-1) is sufficient to trigger activation signals leading to virus reactivation (9).@@@@1@34@@oe@16-12-2010 1023550904@GENIA Treebank@formal@@1@S@In this study, we demonstrate that NF-kappaB nuclear translocation and stimulation of virus production by iHIV-1 were strictly linked to the concentrations of viral proteins used as exogenous stimuli.@@@@1@31@@oe@16-12-2010 1023550905@GENIA Treebank@formal@@1@S@Moreover, we further investigated the physiologic relevance of these observations.@@@@1@12@@oe@16-12-2010 1023550906@GENIA Treebank@formal@@1@S@When submitted to an in vitro CD4 cross-linking by iHIV-1, PBMCs from HIV-1-infected patients were found to produce virus.@@@@1@21@@oe@16-12-2010 1023550907@GENIA Treebank@formal@@1@S@This viral reactivation was associated with increased NF-kappaB nuclear translocation in patients' PBMCs.@@@@1@15@@oe@16-12-2010 1023550908@GENIA Treebank@formal@@1@S@Additionally, virus reactivation in resting PBMCs infected in vitro with HIV-1 was found to be specifically induced by ligands of the CDR2-loop in domain 1 (D1) of CD4 (virus envelope and anti-CD4 monoclonal antibodies).@@@@1@40@@oe@16-12-2010 1023550909@GENIA Treebank@formal@@1@S@In contrast, virus reactivation was not observed following CD4 oligomerization by antibodies that bind other epitopes in D1, including the D1/CDR3-loop.@@@@1@24@@oe@16-12-2010 1023550910@GENIA Treebank@formal@@1@S@Finally, soluble CD4 (sCD4) prevented virus reactivation by D1/CDR2-loop ligands.@@@@1@14@@oe@16-12-2010 1023550911@GENIA Treebank@formal@@1@S@Our results indicate that the signaling events initiated in PBMCs by oligomerization of CD4 at the D1/CDR2-loop can trigger HIV-1 upregulation in infected individuals.@@@@1@25@@oe@16-12-2010 1031881401@GENIA Treebank@formal@@1@S@Bacterial peptidoglycan induces CD14-dependent activation of transcription factors CREB/ATF and AP-1.@@@@1@12@@oe@16-12-2010 1031881402@GENIA Treebank@formal@@1@S@Peptidoglycan (PGN), the major cell wall component of Gram-positive bacteria, induces secretion of cytokines in macrophages through CD14, the pattern recognition receptor that binds lipopolysaccharide and other microbial products.@@@@1@35@@oe@16-12-2010 1031881403@GENIA Treebank@formal@@1@S@To begin to elucidate the mechanisms that regulate the transcription of cytokine genes, we wanted to determine which transcription factors are activated by PGN in mouse RAW264.7 and human THP-1 macrophage cells.@@@@1@34@@oe@16-12-2010 1031881404@GENIA Treebank@formal@@1@S@Our results demonstrated that: (i) PGN induced phosphorylation of the transcription factors ATF-1 and CREB; (ii) ATF-1 and CREB bound DNA as a dimer and induced transcriptional activation of a CRE reporter plasmid, which was inhibited by dominant negative CREB and ATF-1; (iii) PGN induced phosphorylation of c-Jun, protein synthesis of JunB and c-Fos, and transcriptional activation of the AP-1 reporter plasmid, which was inhibited by dominant negative c-Fos; and (iv) PGN-induced activation of CREB/ATF and AP-1 was mediated through CD14.@@@@1@98@@oe@16-12-2010 1031881405@GENIA Treebank@formal@@1@S@This is the first study to demonstrate activation of CREB/ATF and AP-1 transcription factors by PGN or by any other component of Gram-positive bacteria.@@@@1@25@@oe@16-12-2010 1031894201@GENIA Treebank@formal@@1@S@Defining therapeutic targets by using adenovirus: blocking NF-kappaB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators.@@@@1@23@@oe@16-12-2010 1031894202@GENIA Treebank@formal@@1@S@The role of the transcription factor NF-kappaB in the pathogenesis of rheumatoid arthritis has long been a subject of controversy.@@@@1@21@@oe@16-12-2010 1031894203@GENIA Treebank@formal@@1@S@We used an adenoviral technique of blocking NF-kappaB through overexpression of the inhibitory subunit IkappaBalpha, which has the advantage that it can be used in the diseased tissue itself, with >90% of the synovial macrophages, fibroblasts, and T cells infected.@@@@1@47@@oe@16-12-2010 1031894204@GENIA Treebank@formal@@1@S@We found that the spontaneous production of tumor necrosis factor alpha and other pro-inflammatory cytokines is NF-kappaB-dependent in rheumatoid synovial tissue, in contrast to the main anti-inflammatory mediators, like IL-10 and -11, and the IL-1 receptor antagonist.@@@@1@41@@oe@16-12-2010 1031894205@GENIA Treebank@formal@@1@S@Of even more interest, IkappaBalpha overexpression inhibited the production of matrix metalloproteinases 1 and 3 while not affecting their tissue inhibitor.@@@@1@23@@oe@16-12-2010 1031894206@GENIA Treebank@formal@@1@S@Blocking NF-kappaB in the rheumatoid joint thus has a very beneficial profile, reducing both the inflammatory response and the tissue destruction.@@@@1@23@@oe@16-12-2010 1031894207@GENIA Treebank@formal@@1@S@The adenoviral technique described here has widespread applicability, allowing rapid testing of the effects of blocking a potential therapeutic target in either cultures of normal cells or in the diseased tissue itself.@@@@1@34@@oe@16-12-2010 1032036701@GENIA Treebank@formal@@1@S@Nuclear factor-90 of activated T-cells: A double-stranded RNA-binding protein and substrate for the double-stranded RNA-dependent protein kinase, PKR.@@@@1@21@@oe@16-12-2010 1032036702@GENIA Treebank@formal@@1@S@NFAT transcription factors play a central role in initiating T-cell activation through the induction of immediate-early T-cell specific genes including interleukin-2 (IL-2).@@@@1@25@@oe@16-12-2010 1032036703@GENIA Treebank@formal@@1@S@NFAT transcription factors bind to a sequence in the IL-2 enhancer known as the antigen receptor response element 2 (ARRE-2).@@@@1@23@@oe@16-12-2010 1032036704@GENIA Treebank@formal@@1@S@Multiple proteins exhibiting ARRE-2 binding activity have been isolated, including a heterodimer from stimulated T-cell nuclear extracts consisting of Mr = 90 000 (NF90) and Mr = 45 000 (NF45) subunits.@@@@1@37@@oe@16-12-2010 1032036705@GENIA Treebank@formal@@1@S@The subunits of this heterodimer have been cloned, and NF90 was found to encode a protein containing two domains that are predicted to form motifs capable of binding to double-stranded RNA.@@@@1@33@@oe@16-12-2010 1032036706@GENIA Treebank@formal@@1@S@Using in vitro translated polypeptides, we have demonstrated that NF90 specifically binds to double-stranded RNA.@@@@1@17@@oe@16-12-2010 1032036707@GENIA Treebank@formal@@1@S@Furthermore, NF90 was phosphorylated in a double-stranded RNA-dependent manner likely by the interferon-induced, double-stranded RNA-dependent protein kinase, PKR.@@@@1@22@@oe@16-12-2010 1032036708@GENIA Treebank@formal@@1@S@The NF90 protein was found to be expressed not only in T-cells, but also in nonimmune HeLa cells.@@@@1@20@@oe@16-12-2010 1032036709@GENIA Treebank@formal@@1@S@In HeLa cells, the protein was almost exclusively localized to the ribosome salt wash fraction of cell lysates.@@@@1@20@@oe@16-12-2010 1032216001@GENIA Treebank@formal@@1@S@Control of lymphocyte development by the Ikaros gene family.@@@@1@10@@oe@16-12-2010 1032216002@GENIA Treebank@formal@@1@S@Lymphoid cell differentiation relies on precisely orchestrated gene activation and repression events.@@@@1@13@@oe@16-12-2010 1032216003@GENIA Treebank@formal@@1@S@Gene targeting studies have demonstrated crucial roles for the transcription factors Ikaros and Aiolos in regulating multiple stages of B and T cell development.@@@@1@25@@oe@16-12-2010 1032216004@GENIA Treebank@formal@@1@S@Recent experiments suggest that Ikaros and Aiolos set B cell antigen-receptor (BCR)- and TCR-mediated signaling thresholds and that the molecules exist within T cells in nuclear complexes that contain nucleosome remodeling and histone deacetylase activities.@@@@1@39@@oe@16-12-2010 1032705001@GENIA Treebank@formal@@1@S@Cell growth-regulated expression of mammalian MCM5 and MCM6 genes mediated by the transcription factor E2F.@@@@1@16@@oe@16-12-2010 1032705002@GENIA Treebank@formal@@1@S@Initiation of DNA replication requires the function of MCM gene products, which participate in ensuring that DNA replication occurs only once in the cell cycle.@@@@1@27@@oe@16-12-2010 1032705003@GENIA Treebank@formal@@1@S@Expression of all mammalian genes of the MCM family is induced by growth stimulation, unlike yeast, and the mRNA levels peak at G1/S boundary.@@@@1@27@@oe@16-12-2010 1032705004@GENIA Treebank@formal@@1@S@In this study, we examined the transcriptional activities of isolated human MCM gene promoters.@@@@1@16@@oe@16-12-2010 1032705005@GENIA Treebank@formal@@1@S@Human MCM5 and MCM6 promoters with mutation in the E2F sites failed in promoter regulation following serum stimulation and exogenous E2F expression.@@@@1@23@@oe@16-12-2010 1032705006@GENIA Treebank@formal@@1@S@In addition, we identified a novel E2F-like sequence in human MCM6 promoter which cooperates with the authentic E2F sites in E2F-dependent regulation.@@@@1@24@@oe@16-12-2010 1032705007@GENIA Treebank@formal@@1@S@Forced expression of E2F1 could induce expression of all members of the endogenous MCM genes in rat embryonal fibroblast REF52 cells.@@@@1@22@@oe@16-12-2010 1032705008@GENIA Treebank@formal@@1@S@Our results demonstrated that the growth-regulated expression of mammalian MCM5 and MCM6 genes, and presumably other MCM members, is primarily regulated by E2F through binding to multiple E2F sites in the promoters.@@@@1@35@@oe@16-12-2010 1032706401@GENIA Treebank@formal@@1@S@c-Myc and E1A induced cellular sensitivity to activated NK cells involves cytotoxic granules as death effectors.@@@@1@17@@oe@16-12-2010 1032706402@GENIA Treebank@formal@@1@S@The contact of natural killer (NK) cells with foreign cells and with certain virus-infected or tumor cells triggers the cytolytic machinery of NK cells.@@@@1@27@@oe@16-12-2010 1032706403@GENIA Treebank@formal@@1@S@This triggering leads to exocytosis of the cytotoxic NK cell granules.@@@@1@12@@oe@16-12-2010 1032706404@GENIA Treebank@formal@@1@S@The oncoproteins c-Myc and E1A render cells vulnerable to NK cell mediated cytolysis yet the mechanisms of sensitization are not well understood.@@@@1@23@@oe@16-12-2010 1032706405@GENIA Treebank@formal@@1@S@In a model where foreign cells (rat fibroblasts) were cocultured with human IL-2 activated NK cells, we observed that NK cells were capable of efficiently killing their targets only if the cells overexpressed the oncogene c-Myc or E1A.@@@@1@42@@oe@16-12-2010 1032706406@GENIA Treebank@formal@@1@S@Both the parental and the oncogene expressing fibroblasts similarly triggered phosphoinositide hydrolysis in the bound NK cells, demonstrating that NK cells were cytolytically activated in contact with both resistant parental and oncogene expressing sensitive target fibroblasts.@@@@1@38@@oe@16-12-2010 1032706407@GENIA Treebank@formal@@1@S@The cell death was independent of wild-type p53 and was not inhibited by an anti-apoptotic protein EIB19K.@@@@1@18@@oe@16-12-2010 1032706408@GENIA Treebank@formal@@1@S@These results provided evidence that c-Myc and E1A activated the NK cell induced cytolysis at a post-triggering stage of NK cell-target cell interaction.@@@@1@24@@oe@16-12-2010 1032706409@GENIA Treebank@formal@@1@S@In consistence, the c-Myc and E1A overexpressing fibroblasts were more sensitive to the cytolytic effects of isolated NK cell-derived granules than parental cells.@@@@1@25@@oe@16-12-2010 1032706410@GENIA Treebank@formal@@1@S@The data indicate that oncogenes activate the cytotoxicity of NK cell granules.@@@@1@13@@oe@16-12-2010 1032706411@GENIA Treebank@formal@@1@S@This mechanism can have a role in directing the cytolytic action of NK cells towards the virus-infected and cancer cells.@@@@1@21@@oe@16-12-2010 1032810701@GENIA Treebank@formal@@1@S@Apoptosis and growth inhibition in malignant lymphocytes after treatment with arsenic trioxide at clinically achievable concentrations [see comments]@@@@1@20@@oe@16-12-2010 1032810702@GENIA Treebank@formal@@1@S@BACKGROUND: Arsenic trioxide (As2O3) can induce clinical remission in patients with acute promyelocytic leukemia via induction of differentiation and programmed cell death (apoptosis).@@@@1@29@@oe@16-12-2010 1032810703@GENIA Treebank@formal@@1@S@We investigated the effects of As2O3 on a panel of malignant lymphocytes to determine whether growth-inhibitory and apoptotic effects of As2O3 can be observed in these cells at clinically achievable concentrations.@@@@1@32@@oe@16-12-2010 1032810704@GENIA Treebank@formal@@1@S@METHODS: Eight malignant lymphocytic cell lines and primary cultures of lymphocytic leukemia and lymphoma cells were treated with As2O3, with or without dithiothreitol (DTT) or buthionine sulfoximine (BSO) (an inhibitor of glutathione synthesis).@@@@1@42@@oe@16-12-2010 1032810705@GENIA Treebank@formal@@1@S@Apoptosis was assessed by cell morphology, flow cytometry, annexin V protein level, and terminal deoxynucleotidyl transferase labeling of DNA fragments.@@@@1@24@@oe@16-12-2010 1032810706@GENIA Treebank@formal@@1@S@Cellular proliferation was determined by 5-bromo-2'-deoxyuridine incorporation into DNA and flow cytometry and by use of a mitotic arrest assay.@@@@1@21@@oe@16-12-2010 1032810707@GENIA Treebank@formal@@1@S@Mitochondrial transmembrane potential (delta psi(m)) was measured by means of rhodamine 123 staining and flow cytometry.@@@@1@19@@oe@16-12-2010 1032810708@GENIA Treebank@formal@@1@S@Protein expression was assessed by western blot analysis or immunofluorescence.@@@@1@11@@oe@16-12-2010 1032810709@GENIA Treebank@formal@@1@S@RESULTS: Therapeutic concentrations of As2O3 (1-2 microM) had dual effects on malignant lymphocytes: 1) inhibition of growth through adenosine triphosphate (ATP) depletion and prolongation of cell cycle time and 2) induction of apoptosis.@@@@1@42@@oe@16-12-2010 1032810710@GENIA Treebank@formal@@1@S@As2O3-induced apoptosis was preceded by delta psi(m) collapse.@@@@1@9@@oe@16-12-2010 1032810711@GENIA Treebank@formal@@1@S@DTT antagonized and BSO enhanced As2O3-induced ATP depletion, delta psi(m) collapse, and apoptosis.@@@@1@16@@oe@16-12-2010 1032810712@GENIA Treebank@formal@@1@S@Caspase-3 activation, usually resulting from delta psi(m) collapse, was not always associated with As2O3-induced apoptosis.@@@@1@18@@oe@16-12-2010 1032810713@GENIA Treebank@formal@@1@S@As2O3 induced PML (promyelocytic leukemia) protein degradation but did not modulate expression of cell cycle-related proteins, including c-myc, retinoblastoma protein, cyclin-dependent kinase 4, cyclin D1, and p53, or expression of differentiation-related antigens.@@@@1@41@@oe@16-12-2010 1032810714@GENIA Treebank@formal@@1@S@CONCLUSIONS: Substantial growth inhibition and apoptosis without evidence of differentiation were induced in most malignant lymphocytic cells treated with 1-2 microM As2O3.@@@@1@24@@oe@16-12-2010 1032810715@GENIA Treebank@formal@@1@S@As2O3 may prove useful in the treatment of malignant lymphoproliferative disorders.@@@@1@12@@oe@16-12-2010 1032887401@GENIA Treebank@formal@@1@S@Non-steroidal anti-inflammatory drugs inhibit the expression of cytokines and induce HSP70 in human monocytes.@@@@1@15@@oe@16-12-2010 1032887402@GENIA Treebank@formal@@1@S@Recent studies have shown that the non-steroidal anti-inflammatory drugs (NSAIDs) activate heat shock transcription factor (HSF1) from a latent cytoplasmic form to a nuclear, DNA binding state.@@@@1@33@@oe@16-12-2010 1032887403@GENIA Treebank@formal@@1@S@As HSF1 can function as both an activator of heat shock genes and a repressor of non-heat shock genes such as IL1B and c- fos, we have examined the potential role of HSF1 in the effects of NSAIDs on gene expression in a human monocytic cell line THP-1.@@@@1@49@@oe@16-12-2010 1032887404@GENIA Treebank@formal@@1@S@We found that two members of the NSAIDs, sodium salicylate and sulindac repress the IL1B promoter to similar degree to heat shock or HSF1 overexpression.@@@@1@27@@oe@16-12-2010 1032887405@GENIA Treebank@formal@@1@S@In addition, sodium salicylate and additional NSAIDs used at concentrations that activate HSF1 also inhibited the expression of other monocytic genes (TNF-alpha, IL-1beta, IL-6, IL-8, IL-10, ICAM-1) activated by exposure to a pro-inflammatory stimulus (lipopolysaccharide, LPS).@@@@1@48@@oe@16-12-2010 1032887406@GENIA Treebank@formal@@1@S@At least in the case of the IL1B promoter, repression did not seem to involve another factor whose activity is affected by the NSAIDs, NFkappaB as the IL1B promoter fragment used in our studies is not NFkappaB responsive and binds specifically to HSF1.@@@@1@46@@oe@16-12-2010 1032887407@GENIA Treebank@formal@@1@S@Exposure to NSAIDs had a complex effect on HSP gene expression and while sulindac activated the stress responsive HSP70B promoter, sodium salicylate did not.@@@@1@26@@oe@16-12-2010 1032887408@GENIA Treebank@formal@@1@S@In addition, only a subset of the NSAIDs induced HSP70 mRNA species.@@@@1@14@@oe@16-12-2010 1032887409@GENIA Treebank@formal@@1@S@These findings reflect the properties of HSF1 which can be activated to at least two DNA binding forms only one of which activates heat shock promoters and suggest that individual NSAID family members may differentially induce one or other of these forms.@@@@1@43@@oe@16-12-2010 1032887410@GENIA Treebank@formal@@1@S@Overall therefore, exposure to NSAIDs leads to a profound switch in gene expression in monocytic cells, with suppression of genes involved in macrophage activation and induction of stress genes and HSF1 appears to play a regulatory role in these effects.@@@@1@43@@oe@16-12-2010 1032887411@GENIA Treebank@formal@@1@S@Copyright 1999 Academic Press.@@@@1@5@@oe@16-12-2010 1032914701@GENIA Treebank@formal@@1@S@Recognition of NFATp/AP-1 composite elements within genes induced upon the activation of immune cells.@@@@1@15@@oe@16-12-2010 1032914702@GENIA Treebank@formal@@1@S@Composite elements are regulatory modules of promoters or enhancers that consist of binding sites of two different but synergizing transcription factors.@@@@1@22@@oe@16-12-2010 1032914703@GENIA Treebank@formal@@1@S@A well-studied example is nuclear factors of activated T-cell (NFAT) sites which are composite elements of a NFATp/c and an activating protein 1 (AP-1) binding site.@@@@1@31@@oe@16-12-2010 1032914704@GENIA Treebank@formal@@1@S@We have developed a computational approach to identify potential NFAT target genes which (a) comprises an improved method to scan for individual NFAT composite elements; (b) considers positional effects relative to transcription start sites; and (c) involves cluster analysis of potential NFAT composite elements.@@@@1@53@@oe@16-12-2010 1032914705@GENIA Treebank@formal@@1@S@All three steps progressively helpX?ed to discriminate T-cell-specific promoter sequences against other functional regions (coding and intronic sequences) of the same genes, against promoters of muscle-specific genes or against random sequences.@@@@1@35@@oe@16-12-2010 1032914706@GENIA Treebank@formal@@1@S@Using this approach, we identified potential NFAT composite elements in promoters of cytokine genes and their receptors as well as in promoters of genes for AP-1 family members, Ca2+-binding proteins and some other components of the regulatory network operating in activated T-cells and other immune cells.@@@@1@49@@oe@16-12-2010 1032914707@GENIA Treebank@formal@@1@S@The method developed can be adapted to characterize and identify other composite elements as well.@@@@1@16@@oe@16-12-2010 1032914708@GENIA Treebank@formal@@1@S@The program for recognition NFAT composite elements is available through the World Wide Web (http://compel.bionet.nsc.ru/FunSite/CompelScan.html and http://transfac.gbf.de/dbsearch/funsitep/s_comp.html).@@@@1@20@@oe@16-12-2010 1032914709@GENIA Treebank@formal@@1@S@Copyright 1999 Academic Press.@@@@1@5@@oe@16-12-2010 1032962501@GENIA Treebank@formal@@1@S@Disruption of alpha beta but not of gamma delta T cell development by overexpression of the helix-loop-helix protein Id3 in committed T cell progenitors.@@@@1@25@@oe@16-12-2010 1032962502@GENIA Treebank@formal@@1@S@Enforced expression of Id3, which has the capacity to inhibit many basic helix-loop-helix (bHLH) transcription factors, in human CD34(+) hematopoietic progenitor cells that have not undergone T cell receptor (TCR) gene rearrangements inhibits development of the transduced cells into TCRalpha beta and gamma delta cells in a fetal thymic organ culture (FTOC).@@@@1@61@@oe@16-12-2010 1032962503@GENIA Treebank@formal@@1@S@Here we document that overexpression of Id3, in progenitors that have initiated TCR gene rearrangements (pre-T cells), inhibits development into TCRalpha beta but not into TCRgamma delta T cells.@@@@1@34@@oe@16-12-2010 1032962504@GENIA Treebank@formal@@1@S@Furthermore, Id3 impedes expression of recombination activating genes and downregulates pre-Talpha mRNA.@@@@1@14@@oe@16-12-2010 1032962505@GENIA Treebank@formal@@1@S@These observations suggest possible mechanisms by which Id3 overexpression can differentially affect development of pre-T cells into TCRalpha beta and gamma delta cells.@@@@1@24@@oe@16-12-2010 1032962506@GENIA Treebank@formal@@1@S@We also observed that cell surface CD4(-)CD8(-)CD3(-) cells with rearranged TCR genes developed from Id3-transduced but not from control-transduced pre-T cells in an FTOC.@@@@1@25@@oe@16-12-2010 1032962507@GENIA Treebank@formal@@1@S@These cells had properties of both natural killer (NK) and pre-T cells.@@@@1@15@@oe@16-12-2010 1032962508@GENIA Treebank@formal@@1@S@These findings suggest that bHLH factors are required to control T cell development after the T/NK developmental checkpoint.@@@@1@19@@oe@16-12-2010 1032962601@GENIA Treebank@formal@@1@S@Rel/NF-kappaB can trigger the Notch signaling pathway by inducing the expression of Jagged1, a ligand for Notch receptors.@@@@1@20@@oe@16-12-2010 1032962602@GENIA Treebank@formal@@1@S@Jagged1 belongs to the DSL family of ligands for Notch receptors that control the proliferation and differentiation of various cell lineages.@@@@1@22@@oe@16-12-2010 1032962603@GENIA Treebank@formal@@1@S@However, little is known about the transcription factors that regulate its expression.@@@@1@14@@oe@16-12-2010 1032962604@GENIA Treebank@formal@@1@S@Here, we show that Jagged1 is a Rel/NF-kappaB-responsive gene.@@@@1@11@@oe@16-12-2010 1032962605@GENIA Treebank@formal@@1@S@Both c-Rel and RelA induced jagged1 gene expression, whereas a mutant defective for transactivation did not.@@@@1@18@@oe@16-12-2010 1032962606@GENIA Treebank@formal@@1@S@Importantly, jagged1 transcripts were also upregulated by endogenous NF-kappaB activation and this effect was inhibited by a dominant mutant of IkappaBalpha, a physiological inhibitor of NF-kappaB.@@@@1@29@@oe@16-12-2010 1032962607@GENIA Treebank@formal@@1@S@Cell surface expression of Jagged1 in c-Rel-expressing cell monolayers led to a functional interaction with lymphocytes expressing the Notch1/TAN-1 receptor.@@@@1@21@@oe@16-12-2010 1032962608@GENIA Treebank@formal@@1@S@This correlated with the initiation of signaling downstream of Notch, as evidenced by increased levels of HES-1 transcripts in co-cultivated T cells and of CD23 transcripts in co-cultivated B cells.@@@@1@32@@oe@16-12-2010 1032962609@GENIA Treebank@formal@@1@S@Consistent with its Rel/NF-kappaB-dependent induction, Jagged1 was found to be highly expressed in splenic B cells where c-Rel is expressed constitutively.@@@@1@23@@oe@16-12-2010 1032962610@GENIA Treebank@formal@@1@S@These results demonstrate that c-Rel can trigger the Notch signaling pathway in neighboring cells by inducing jagged1 gene expression, and suggest a role for Jagged1 in B-cell activation, differentiation or function.@@@@1@34@@oe@16-12-2010 1032962611@GENIA Treebank@formal@@1@S@These findings also highlight the potential for an interplay between the Notch and NF-kappaB signaling pathways in the immune system.@@@@1@21@@oe@16-12-2010 1032984501@GENIA Treebank@formal@@1@S@Transcriptional control of the IL-5 gene by human helper T cells: IL-5 synthesis is regulated independently from IL-2 or IL-4 synthesis.@@@@1@23@@oe@16-12-2010 1032984502@GENIA Treebank@formal@@1@S@BACKGROUND: IL-5 is fundamentally involved in eosinophilic inflammation.@@@@1@10@@oe@16-12-2010 1032984503@GENIA Treebank@formal@@1@S@Control of IL-5 production may be effective for the management of allergic diseases.@@@@1@14@@oe@16-12-2010 1032984504@GENIA Treebank@formal@@1@S@OBJECTIVE: We aimed to find the transcriptional mechanisms that regulate the IL-5 gene to selectively control IL-5 synthesis.@@@@1@20@@oe@16-12-2010 1032984505@GENIA Treebank@formal@@1@S@METHODS: Allergen-specific T-cell clones and T-cell hybridomas were established from the peripheral blood lymphocytes of patients with asthma, and the transcriptional regulation of the IL-5 gene was investigated with transient transfection and electrophoretic mobility shift analysis.@@@@1@39@@oe@16-12-2010 1032984506@GENIA Treebank@formal@@1@S@RESULTS: A human IL-5 promoter/enhancer-luciferase gene construct, pIL-5(-511)Luc, was transcribed on activation of IL-5-producing T-cell clones, but not IL-5-nonproducing clones.@@@@1@26@@oe@16-12-2010 1032984507@GENIA Treebank@formal@@1@S@pIL-5(-511)Luc was transcribed by T-cell hybridomas derived from fusion between IL-5-producing T-cell clones and an IL-5 gene-nonexpressing T-cell line, but not by hybridomas derived from IL-5-nonproducing T-cell clones.@@@@1@31@@oe@16-12-2010 1032984508@GENIA Treebank@formal@@1@S@IL-5 synthesis was not only induced by T-cell receptor stimulation but also by IL-2 receptor stimulation.@@@@1@17@@oe@16-12-2010 1032984509@GENIA Treebank@formal@@1@S@Binding of NF-AT, NF-kappaB, and AP-1 was induced by T-cell receptor (TcR) stimulation, although there was no significant upregulation of binding by IL-2 stimulation.@@@@1@30@@oe@16-12-2010 1032984510@GENIA Treebank@formal@@1@S@CONCLUSION: IL-5 synthesis by human helper T cells is regulated at the transcriptional level.@@@@1@16@@oe@16-12-2010 1032984511@GENIA Treebank@formal@@1@S@A unique transcriptional mechanism distinct from those regulating the IL-2 or IL-4 genes seems to control the IL-5 gene.@@@@1@20@@oe@16-12-2010 1032984512@GENIA Treebank@formal@@1@S@Selective regulation of IL-5 gene transcription may be useful for treating eosinophlic inflammation.@@@@1@14@@oe@16-12-2010 1032995801@GENIA Treebank@formal@@1@S@Regulation of low shear flow-induced HAEC VCAM-1 expression and monocyte adhesion.@@@@1@12@@oe@16-12-2010 1032995802@GENIA Treebank@formal@@1@S@We recently reported that prolonged exposure of human aortic endothelial cells (HAEC) to low shear stress flow patterns is associated with a sustained increase in the activated form of the transcriptional regulator nuclear factor-kappaB (NF-kappaB).@@@@1@40@@oe@16-12-2010 1032995803@GENIA Treebank@formal@@1@S@Here we investigate the hypothesis that low shear-induced activation of NF-kappaB is responsible for enhanced expression of vascular cell adhesion molecule (VCAM-1) resulting in augmented endothelial cell-monocyte (EC-Mn) adhesion and that this activation is dependent on intracellular oxidant activity.@@@@1@44@@oe@16-12-2010 1032995804@GENIA Treebank@formal@@1@S@Before exposure to low shear (2 dyn/cm2) for 6 h, HAEC were preincubated with or without the antioxidants pyrrolidine dithiocarbamate (PDTC) or N-acetyl-L-cysteine (NAC).@@@@1@32@@oe@16-12-2010 1032995805@GENIA Treebank@formal@@1@S@PDTC strongly inhibited low shear-induced activation of NF-kappaB, expression of VCAM-1, and EC-Mn adhesion.@@@@1@17@@oe@16-12-2010 1032995806@GENIA Treebank@formal@@1@S@Paradoxically, NAC exerted a positive effect on low shear-induced VCAM-1 expression and EC-Mn adhesion and only slightly downregulated NF-kappaB activation.@@@@1@22@@oe@16-12-2010 1032995807@GENIA Treebank@formal@@1@S@However, cytokine-induced NF-kappaB activation and VCAM-1 expression are blocked by both PDTC and NAC.@@@@1@16@@oe@16-12-2010 1032995808@GENIA Treebank@formal@@1@S@These data suggest that NF-kappaB plays a key role in low shear-induced VCAM-1 expression and that pathways mediating low shear- and cytokine-induced EC-Mn adhesion may be differentially regulated.@@@@1@29@@oe@16-12-2010 1033018901@GENIA Treebank@formal@@1@S@Nuclear localization and formation of beta-catenin-lymphoid enhancer factor 1 complexes are not sufficient for activation of gene expression.@@@@1@19@@oe@16-12-2010 1033018902@GENIA Treebank@formal@@1@S@In response to activation of the Wnt signaling pathway, beta-catenin accumulates in the nucleus, where it cooperates with LEF/TCF (for lymphoid enhancer factor and T-cell factor) transcription factors to activate gene expression.@@@@1@37@@oe@16-12-2010 1033018903@GENIA Treebank@formal@@1@S@The mechanisms by which beta-catenin undergoes this shift in location and participates in activation of gene transcription are unknown.@@@@1@20@@oe@16-12-2010 1033018904@GENIA Treebank@formal@@1@S@We demonstrate here that beta-catenin can be imported into the nucleus independently of LEF/TCF binding, and it may also be exported from nuclei.@@@@1@25@@oe@16-12-2010 1033018905@GENIA Treebank@formal@@1@S@We have introduced a small deletion within beta-catenin (Delta19) that disrupts binding to LEF-1, E-cadherin, and APC but not axin.@@@@1@25@@oe@16-12-2010 1033018906@GENIA Treebank@formal@@1@S@This Delta19 beta-catenin mutant localizes to the nucleus because it may not be efficiently sequestered in the cytoplasm.@@@@1@19@@oe@16-12-2010 1033018907@GENIA Treebank@formal@@1@S@The nuclear localization of Delta19 definitively demonstrates that the mechanisms by which beta-catenin localizes in the nucleus are completely independent of LEF/TCF factors.@@@@1@24@@oe@16-12-2010 1033018908@GENIA Treebank@formal@@1@S@beta-Catenin and LEF-1 complexes can activate reporter gene expression in a transformed T-lymphocyte cell line (Jurkat) but not in normal T lymphocytes, even though both factors are nuclear.@@@@1@32@@oe@16-12-2010 1033018909@GENIA Treebank@formal@@1@S@Thus, localization of both factors to the nucleus is not sufficient for activation of gene expression.@@@@1@18@@oe@16-12-2010 1033018910@GENIA Treebank@formal@@1@S@Excess beta-catenin can squelch reporter gene activation by LEF-1-beta-catenin complexes but not activation by the transcription factor VP16.@@@@1@19@@oe@16-12-2010 1033018911@GENIA Treebank@formal@@1@S@Taken together, these data suggest that a third component is necessary for gene activation and that this third component may vary with cell type.@@@@1@26@@oe@16-12-2010 1033027401@GENIA Treebank@formal@@1@S@Paradoxical priming effects of IL-10 on cytokine production.@@@@1@9@@oe@16-12-2010 1033027402@GENIA Treebank@formal@@1@S@IL-10 is a well-known immunosuppressive and/or anti-inflammatory cytokine.@@@@1@9@@oe@16-12-2010 1033027403@GENIA Treebank@formal@@1@S@However, we report in vitro experimental studies in which IL-10 primed leukocytes and led to an enhanced production of tumor necrosis factor (TNF) upon further stimulation by lipopolysaccharide (LPS).@@@@1@35@@oe@16-12-2010 1033027404@GENIA Treebank@formal@@1@S@Monocytes and peripheral blood mononuclear cells (PBMC) prepared from whole blood maintained for 20 h at 37 degrees C in the presence of recombinant human IL-10 had an enhanced capacity to produce TNF in response to LPS.@@@@1@40@@oe@16-12-2010 1033027405@GENIA Treebank@formal@@1@S@In addition to TNF, LPS-induced IL-6 and spontaneous IL-1ra production were also enhanced.@@@@1@15@@oe@16-12-2010 1033027406@GENIA Treebank@formal@@1@S@When isolated PBMC were first cultured for 20 h in the presence of IL-10 on Teflon to prevent adherence, washed to remove IL-10 and then further cultured in plastic dishes for an additional 20 h in the presence of LPS or IL-1beta, an enhanced release of TNF was observed.@@@@1@52@@oe@16-12-2010 1033027407@GENIA Treebank@formal@@1@S@This was not the case when PBMC were pre-cultured in plastic multidishes in the presence of IL-10.@@@@1@18@@oe@16-12-2010 1033027408@GENIA Treebank@formal@@1@S@TNF mRNA expression induced by LPS was decreased when the pre-treatment of PBMC with IL-10 was performed on plastic, whereas this was not the case when cells were pre-cultured with IL-10 on Teflon.@@@@1@35@@oe@16-12-2010 1033027409@GENIA Treebank@formal@@1@S@Furthermore, NFkappaB translocation following LPS activation was higher after IL-10 pre-treatment on Teflon than on plastic.@@@@1@18@@oe@16-12-2010 1033027410@GENIA Treebank@formal@@1@S@Interestingly, an enhanced frequency of CD16 and CD68(+) cells among the CD14(+) cells was observed in the presence of IL-10, independently of the pre-culture conditions of the PBMC.@@@@1@31@@oe@16-12-2010 1033027411@GENIA Treebank@formal@@1@S@Altogether, these results indicate that the IL-10-induced up-regulation of cytokine production depends on the prevention of monocyte adherence by red cells in the whole blood assays or by cultures of PBMC on Teflon.@@@@1@35@@oe@16-12-2010 1033027412@GENIA Treebank@formal@@1@S@In contrast, the adherence parameter has no effect on the IL-10-induced modulation of some monocyte surface markers.@@@@1@19@@oe@16-12-2010 1033039601@GENIA Treebank@formal@@1@S@A role for RanBP1 in the release of CRM1 from the nuclear pore complex in a terminal step of nuclear export.@@@@1@22@@oe@16-12-2010 1033039602@GENIA Treebank@formal@@1@S@We recently developed an assay in which nuclear export of the shuttling transcription factor NFAT (nuclear factor of activated T cells) can be reconstituted in permeabilized cells with the GTPase Ran and the nuclear export receptor CRM1.@@@@1@40@@oe@16-12-2010 1033039603@GENIA Treebank@formal@@1@S@We have now used this assay to identify another export factor.@@@@1@12@@oe@16-12-2010 1033039604@GENIA Treebank@formal@@1@S@After preincubation of permeabilized cells with a Ran mutant that cannot hydrolyze GTP (RanQ69L), cytosol supports NFAT export, but CRM1 and Ran alone do not.@@@@1@31@@oe@16-12-2010 1033039605@GENIA Treebank@formal@@1@S@The RanQ69L preincubation leads to accumulation of CRM1 at the cytoplasmic periphery of the nuclear pore complex (NPC) in association with the p62 complex and Can/Nup214.@@@@1@29@@oe@16-12-2010 1033039606@GENIA Treebank@formal@@1@S@RanGTP-dependent association of CRM1 with these nucleoporins was reconstituted in vitro.@@@@1@12@@oe@16-12-2010 1033039607@GENIA Treebank@formal@@1@S@By biochemical fractionation and reconstitution, we showed that RanBP1 restores nuclear export after the RanQ69L preincubation.@@@@1@18@@oe@16-12-2010 1033039608@GENIA Treebank@formal@@1@S@It also stimulates nuclear export in cells that have not been preincubated with RanQ69L.@@@@1@15@@oe@16-12-2010 1033039609@GENIA Treebank@formal@@1@S@RanBP1 as well as Ran-binding domains of the cytoplasmic nucleoporin RanBP2 promote the release of CRM1 from the NPC.@@@@1@20@@oe@16-12-2010 1033039610@GENIA Treebank@formal@@1@S@Taken together, our results indicate that RanGTP is important for the targeting of export complexes to the cytoplasmic side of the NPC and that RanBP1 and probably RanBP2 are involved in the dissociation of nuclear export complexes from the NPC in a terminal step of transport.@@@@1@48@@oe@16-12-2010 1033156401@GENIA Treebank@formal@@1@S@Expression of Th1 and Th2 type cytokines responding to HBsAg and HBxAg in chronic hepatitis B patients.@@@@1@18@@oe@16-12-2010 1033156402@GENIA Treebank@formal@@1@S@The cytokine pattern on viral antigen recognition is believed to exert a profound influence on the resolution of viral infections and viral clearance.@@@@1@24@@oe@16-12-2010 1033156403@GENIA Treebank@formal@@1@S@This study was initiated to investigate whether a cytokine imbalance oriented toward Th2 type response plays a role in chronic hepatitis B.@@@@1@23@@oe@16-12-2010 1033156404@GENIA Treebank@formal@@1@S@Cytokine profiles of peripheral blood mononuclear cells associated with chronic hepatitis B were analysed by RT-PCR.@@@@1@17@@oe@16-12-2010 1033156405@GENIA Treebank@formal@@1@S@Upon HBsAg stimulation, expression of IFN-gamma, IL-2, IL-4, and IL-10 was detected in 41%, 8%, 41%, and 50% of the patients, respectively.@@@@1@35@@oe@16-12-2010 1033156406@GENIA Treebank@formal@@1@S@Among these cytokines, the expression of IFN-gamma was associated with high levels of serum AST/ALT.@@@@1@17@@oe@16-12-2010 1033156407@GENIA Treebank@formal@@1@S@However, we could not prove that Th2 type cytokines had a protective effect on hepatocytes.@@@@1@17@@oe@16-12-2010 1033156408@GENIA Treebank@formal@@1@S@Upon HBxAg stimulation, there was no recognizable association of cytokine patterns with AST/ALT levels.@@@@1@16@@oe@16-12-2010 1033156409@GENIA Treebank@formal@@1@S@In conclusion, production of a Th1 cytokine, IFN-gamma, by HBsAg-reactive cells was associated with hepatocyte damage in chronic hepatitis B, while no counteracting effect of Th2 cytokines produced by those cells was observed.@@@@1@38@@oe@16-12-2010 1033198901@GENIA Treebank@formal@@1@S@Different sequence requirements for expression in erythroid and megakaryocytic cells within a regulatory element upstream of the GATA-1 gene.@@@@1@20@@oe@16-12-2010 1033198902@GENIA Treebank@formal@@1@S@The lineage-restricted transcription factor GATA-1 is required for differentiation of erythroid and megakaryocytic cells.@@@@1@15@@oe@16-12-2010 1033198903@GENIA Treebank@formal@@1@S@We have localized a 317 base pair cis-acting regulatory element, HS I, associated with a hematopoietic-specific DNase I hypersensitive site, which lies approx. 3.7 kilobases upstream of the murine hematopoietic-specific GATA-1 IE promoter.@@@@1@37@@oe@16-12-2010 1033198904@GENIA Treebank@formal@@1@S@HS I directs high-level expression of reporter GATA-1/lacZ genes to primitive and definitive erythroid cells and megakaryocytes in transgenic mice.@@@@1@21@@oe@16-12-2010 1033198905@GENIA Treebank@formal@@1@S@Comparative sequence analysis of HS I between human and mouse shows approx. 63% nucleotide identity with a more conserved core of 169 base pairs (86% identity).@@@@1@31@@oe@16-12-2010 1033198906@GENIA Treebank@formal@@1@S@This core contains a GATA site separated by 10 base pairs from an E-box motif.@@@@1@16@@oe@16-12-2010 1033198907@GENIA Treebank@formal@@1@S@The composite motif binds a multi-protein hematopoietic-specific transcription factor complex which includes GATA-1, SCL/tal-1, E2A, Lmo2 and Ldb-1.@@@@1@22@@oe@16-12-2010 1033198908@GENIA Treebank@formal@@1@S@Point mutations of the GATA site abolishes HS I function, whereas mutation of the E-box motif still allows reporter gene expression in both lineages.@@@@1@26@@oe@16-12-2010 1033198909@GENIA Treebank@formal@@1@S@Strict dependence of HS I activity on a GATA site implies that assembly of a protein complex containing a GATA-factor, presumably GATA-1 or GATA-2, is critical to activating or maintaining its function.@@@@1@35@@oe@16-12-2010 1033198910@GENIA Treebank@formal@@1@S@Further dissection of the 317 base pair region demonstrates that, whereas all 317 base pairs are required for expression in megakaryocytes, only the 5' 62 base pairs are needed for erythroid-specific reporter expression.@@@@1@36@@oe@16-12-2010 1033198911@GENIA Treebank@formal@@1@S@These findings demonstrate differential lineage requirements for expression within the HS I element.@@@@1@14@@oe@16-12-2010 1033947501@GENIA Treebank@formal@@1@S@Monocyte arrest and transmigration on inflamed endothelium in shear flow is inhibited by adenovirus-mediated gene transfer of IkappaB-alpha.@@@@1@19@@oe@16-12-2010 1033947502@GENIA Treebank@formal@@1@S@Mobilization of nuclear factor-kappaB (NF-kappaB) activates transcription of genes encoding endothelial adhesion molecules and chemokines that contribute to monocyte infiltration critical in atherogenesis.@@@@1@26@@oe@16-12-2010 1033947503@GENIA Treebank@formal@@1@S@Inhibition of NF-kappaB has been achieved by pharmacological and genetic approaches; however, monocyte interactions with activated endothelium in shear flow following gene transfer of the NF-kappaB inhibitor IkappaB-alpha have not been studied.@@@@1@35@@oe@16-12-2010 1033947504@GENIA Treebank@formal@@1@S@We found that overexpression of IkappaB-alpha in endothelial cells using a recombinant adenovirus prevented tumor necrosis factor-alpha (TNF-alpha)-induced degradation of IkappaB-alpha and suppressed the upregulation of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin mRNA and surface protein expression and the upregulation of transcripts for the chemokines monocyte chemoattractant protein 1 (MCP-1) and growth-related activity-alpha (GRO-alpha) by TNF-alpha.@@@@1@75@@oe@16-12-2010 1033947505@GENIA Treebank@formal@@1@S@This was associated with a reduction in endothelial MCP-1 secretion and GRO-alpha immobilization.@@@@1@14@@oe@16-12-2010 1033947506@GENIA Treebank@formal@@1@S@Adhesion assays under physiological shear flow conditions showed that firm arrest, spreading, and transmigration of monocytes on TNF-alpha-activated endothelium was markedly inhibited by IkappaB-alpha overexpression.@@@@1@28@@oe@16-12-2010 1033947507@GENIA Treebank@formal@@1@S@Inhibition with monoclonal antibodies and peptide antagonists inferred that this was due to reduced expression of Ig integrin ligand as well as of chemokines specifically involved in these events.@@@@1@30@@oe@16-12-2010 1033947508@GENIA Treebank@formal@@1@S@In contrast, rolling of monocytes was increased by IkappaB-alpha transfer and was partly mediated by P-selectin; however, it appeared to be unaffected by the inhibition of E-selectin induction.@@@@1@32@@oe@16-12-2010 1033947509@GENIA Treebank@formal@@1@S@Thus, our data provide novel evidence that selective modulation of NF-kappaB by adenoviral transfer of IkappaB-alpha impairs the expression of multiple endothelial gene products required for subsequent monocyte arrest and emigration in shear flow and thus for monocyte infiltration in atherosclerotic plaques.@@@@1@44@@oe@16-12-2010 1033948201@GENIA Treebank@formal@@1@S@Protein kinase B (c-Akt), phosphatidylinositol 3-kinase, and STAT5 are activated by erythropoietin (EPO) in HCD57 erythroid cells but are constitutively active in an EPO-independent, apoptosis-resistant subclone (HCD57-SREI cells).@@@@1@38@@oe@16-12-2010 1033948202@GENIA Treebank@formal@@1@S@We found that erythropoietin (EPO) and stem cell factor (SCF) activated protein kinase B (PKB/Akt) in EPO-dependent HCD57 erythroid cells.@@@@1@27@@oe@16-12-2010 1033948203@GENIA Treebank@formal@@1@S@To better understand signals controlling proliferation and viability, erythroid cells that resist apoptosis in the absence of EPO were subcloned and characterized (HCD57-SREI cells).@@@@1@28@@oe@16-12-2010 1033948204@GENIA Treebank@formal@@1@S@Constitutive activations of PKB/Akt, STAT5a, and STAT5b were noted in these EPO-independent cells.@@@@1@16@@oe@16-12-2010 1033948205@GENIA Treebank@formal@@1@S@PI3-kinase activity was an upstream activator of PKB/Akt because the PI3-kinase inhibitor LY294002 blocked both constitutive PKB/Akt and factor-dependent PKB/Akt activity.@@@@1@22@@oe@16-12-2010 1033948206@GENIA Treebank@formal@@1@S@The LY294002 study showed that proliferation and viability of both HCD57-SREI and HCD57 cells correlated with the activity of PKB/Akt; however, PKB/Akt activity alone did not protect these cells from apoptosis.@@@@1@34@@oe@16-12-2010 1033948207@GENIA Treebank@formal@@1@S@Treatment of HCD57 cells with SCF also activated PKB/Akt, but did not protect from apoptosis.@@@@1@17@@oe@16-12-2010 1033948208@GENIA Treebank@formal@@1@S@This result suggested that PKB/PI3-kinase activity is necessary but not sufficient to promote viability and/or proliferation.@@@@1@17@@oe@16-12-2010 1033948209@GENIA Treebank@formal@@1@S@Constitutive STAT5 activity, activated through an unknown pathway not including JAK2 or EPOR, may act in concert with the constitutive PI3-kinase/PKB/Akt pathway to protect the EPO-independent HCD57-SREI cells from apoptosis and promote limited proliferation.@@@@1@37@@oe@16-12-2010 1034717501@GENIA Treebank@formal@@1@S@SLP-76 and Vav function in separate, but overlapping pathways to augment interleukin-2 promoter activity.@@@@1@16@@oe@16-12-2010 1034717502@GENIA Treebank@formal@@1@S@SLP-76 and Vav, two hematopoietic cell specific molecules, are critical for T cell development and activation.@@@@1@19@@oe@16-12-2010 1034717503@GENIA Treebank@formal@@1@S@Following T cell antigen receptor stimulation, SLP-76 and Vav both undergo tyrosine phosphorylation and associate with each other via the SH2 domain of Vav and phosphorylated tyrosines of SLP-76.@@@@1@31@@oe@16-12-2010 1034717504@GENIA Treebank@formal@@1@S@Furthermore, SLP-76 and Vav have a synergistic effect on interleukin (IL)-2 promoter activity in T cells.@@@@1@21@@oe@16-12-2010 1034717505@GENIA Treebank@formal@@1@S@In this report, we show that two tyrosines, Tyr-113 and Tyr-128, of SLP-76 are required for its binding to Vav, both in vitro and in intact cells.@@@@1@32@@oe@16-12-2010 1034717506@GENIA Treebank@formal@@1@S@Surprisingly, we find also that the interaction between SLP-76 and Vav is not required for their cooperation in augmenting IL-2 promoter activity, as the two molecules appear to function in different signaling pathways upstream of IL-2 gene expression.@@@@1@41@@oe@16-12-2010 1034717507@GENIA Treebank@formal@@1@S@Overexpression of SLP-76 in the Jurkat T cell line potentiates the activities of both nuclear factor of activated T cells and AP-1 transcription factors.@@@@1@25@@oe@16-12-2010 1034717508@GENIA Treebank@formal@@1@S@In contrast, overexpression of Vav leads to enhanced nuclear factor of activated T cells activity without affecting AP-1.@@@@1@20@@oe@16-12-2010 1034717509@GENIA Treebank@formal@@1@S@Additionally, overexpression of Vav, but not SLP-76, augments CD28-induced IL-2 promoter activity.@@@@1@16@@oe@16-12-2010 1034717510@GENIA Treebank@formal@@1@S@These findings suggest that the synergy between SLP-76 and Vav in regulating IL-2 gene expression reflects the cooperation between different signaling pathways.@@@@1@23@@oe@16-12-2010 1034834001@GENIA Treebank@formal@@1@S@Human T-cell leukemia virus type 1 Tax protein induces the expression of STAT1 and STAT5 genes in T-cells.@@@@1@19@@oe@16-12-2010 1034834002@GENIA Treebank@formal@@1@S@Human T-cell leukemia virus type 1 (HTLV-1) Tax transforms normal T-cells in the presence of interleukin (IL)-2 in vitro.@@@@1@25@@oe@16-12-2010 1034834003@GENIA Treebank@formal@@1@S@STAT is a family of transcription factors that play a pivotal role in cytokine-induced functions of a various type of cells.@@@@1@22@@oe@16-12-2010 1034834004@GENIA Treebank@formal@@1@S@We investigated the involvement of STATs in the transformation of T-cells by HTLV-1.@@@@1@14@@oe@16-12-2010 1034834005@GENIA Treebank@formal@@1@S@HTLV-1-transformed T-cell lines expressed higher amounts of STAT1, STAT3 and STAT5 RNA and proteins than virus-negative T cells.@@@@1@20@@oe@16-12-2010 1034834006@GENIA Treebank@formal@@1@S@The expression of STAT1 and STAT5 in a human T-cell line was induced by Tax.@@@@1@16@@oe@16-12-2010 1034834007@GENIA Treebank@formal@@1@S@IL-2 induced the DNA binding activity of STAT3 and STAT5 of a HTLV-1-transformed cell line and then stimulated its proliferation.@@@@1@21@@oe@16-12-2010 1034834008@GENIA Treebank@formal@@1@S@In contrast, IL-2 did neither in a cell line lacking STAT3 and STAT5.@@@@1@15@@oe@16-12-2010 1034834009@GENIA Treebank@formal@@1@S@The expression of STAT1, STAT3 and STAT5 mRNAs were also induced by a T-cell mitogen in normal human peripheral blood mononuclear cells.@@@@1@24@@oe@16-12-2010 1034834010@GENIA Treebank@formal@@1@S@Our results suggest that the induction of STAT1 and STAT5 by Tax enhances cytokine-induced functions of virus-infected T-cells, hence the induction may play a role in IL-2-dependent transformation steps of T-cells by HTLV-1.@@@@1@35@@oe@16-12-2010 1034951301@GENIA Treebank@formal@@1@S@Targeted remodeling of human beta-globin promoter chromatin structure produces increased expression and decreased silencing.@@@@1@15@@oe@16-12-2010 1034951302@GENIA Treebank@formal@@1@S@The chromatin structure of the human beta-globin gene locus assumes a transcriptionally-active conformation in erythroid cells.@@@@1@17@@oe@16-12-2010 1034951303@GENIA Treebank@formal@@1@S@One feature of this chromatin reorganization is the formation of DNase 1 hypersensitive sites in the regions of active globin gene promoters.@@@@1@23@@oe@16-12-2010 1034951304@GENIA Treebank@formal@@1@S@This reorganization requires the globin locus control region and is associated with normal expression of the beta-like globin genes.@@@@1@20@@oe@16-12-2010 1034951305@GENIA Treebank@formal@@1@S@To determine whether it is possible to artificially enhance the opening of the chromatin structure of a minimal beta-globin promoter, we placed a 101bp, erythroid-specific DNase 1 hypersensitive site-forming element (HSFE) immediately upstream of the beta-globin promoter and gene.@@@@1@44@@oe@16-12-2010 1034951306@GENIA Treebank@formal@@1@S@This element includes binding sites for NF-E2, AP-1, GATA-1 and Sp-1.@@@@1@14@@oe@16-12-2010 1034951307@GENIA Treebank@formal@@1@S@Constructs were stably transfected into murine erythroleukemia cells and promoter chromatin structure and gene expression were analyzed.@@@@1@18@@oe@16-12-2010 1034951308@GENIA Treebank@formal@@1@S@The HSFE induced an area of enhanced DNase 1 hypersensitivity extending from the transcriptional start site to -300bp of the artificial promoter and significantly increased the proportion of beta-globin promoters in an open chromatin configuration.@@@@1@36@@oe@16-12-2010 1034951309@GENIA Treebank@formal@@1@S@This remodeling of promoter chromatin structure resulted in 3-fold increases in beta-globin gene transcription and induction, and inhibited long-term beta-globin gene silencing.@@@@1@24@@oe@16-12-2010 1034951310@GENIA Treebank@formal@@1@S@These results indicate that a relatively small cis-acting element is able to enhance remodeling of promoter chromatin structure resulting in increased beta-globin gene expression.@@@@1@25@@oe@16-12-2010 1035224701@GENIA Treebank@formal@@1@S@Selection and long-term persistence of reactive CTL clones during an EBV chronic response are determined by avidity, CD8 variable contribution compensating for differences in TCR affinities.@@@@1@28@@oe@16-12-2010 1035224702@GENIA Treebank@formal@@1@S@Recent studies have suggested that the diversity of TCR repertoire after primary immunization is conserved in memory T cells and that a progressive narrowing of this repertoire may take place during recall infections.@@@@1@34@@oe@16-12-2010 1035224703@GENIA Treebank@formal@@1@S@It now remains to be investigated which parameters determine the repertoire of the memory response and possibly restrict its diversity after subsequent antigenic challenges.@@@@1@25@@oe@16-12-2010 1035224704@GENIA Treebank@formal@@1@S@To address this question, we took advantage of a panel of CD8+ T cell clones from the joint of a rheumatoid arthritis patient and selected for their reactivity against a single MHC/peptide complex.@@@@1@35@@oe@16-12-2010 1035224705@GENIA Treebank@formal@@1@S@Characterization of both TCR chains documented a great diversity among those clones and the persistence of clonotypes over a 2-yr period.@@@@1@22@@oe@16-12-2010 1035224706@GENIA Treebank@formal@@1@S@Strikingly, despite the observed repertoire heterogeneity, all clones displayed a narrow range of MHC/peptide density requirements in cytotoxicity assays (ED50 between 9 and 36 nM).@@@@1@30@@oe@16-12-2010 1035224707@GENIA Treebank@formal@@1@S@TCR affinities were then indirectly estimated by blocking CD8 interaction with an anti-CD8 mAb.@@@@1@15@@oe@16-12-2010 1035224708@GENIA Treebank@formal@@1@S@We found a wide range of TCR affinities among the different clonotypes that segregated with Vbeta usage.@@@@1@18@@oe@16-12-2010 1035224709@GENIA Treebank@formal@@1@S@We thus propose that during an in vivo chronic response, a narrow range of avidity of the TCR-CD8 complex conditions long-term clonotype persistence, and that the level of CD8 contribution is adjusted to keep clonotypes with variable TCR affinities within this avidity window.@@@@1@46@@oe@16-12-2010 1035225801@GENIA Treebank@formal@@1@S@In vivo inhibition of NF-kappa B in T-lineage cells leads to a dramatic decrease in cell proliferation and cytokine production and to increased cell apoptosis in response to mitogenic stimuli, but not to abnormal thymopoiesis.@@@@1@37@@oe@16-12-2010 1035225802@GENIA Treebank@formal@@1@S@To understand the role of NF-kappa B complexes in T cell development and activation, we have generated transgenic mice in which RelA and c-Rel complexes were selectively inhibited in the T-lineage cells by specific expression of a trans-dominant form of I kappa B alpha.@@@@1@46@@oe@16-12-2010 1035225803@GENIA Treebank@formal@@1@S@Transgene expression did not affect the thymic development, but led to lowered numbers of splenic T cells and to a dramatic decrease in the ex vivo proliferative response of splenic T lymphocytes.@@@@1@34@@oe@16-12-2010 1035225804@GENIA Treebank@formal@@1@S@Analysis of IL-2 and IL-2R alpha expression demonstrated that the perturbation of the proliferation response was not attributable to an abnormal expression of these genes.@@@@1@26@@oe@16-12-2010 1035225805@GENIA Treebank@formal@@1@S@In contrast, expression of IL-4, IL-10, and IFN-gamma was strongly inhibited in the transgenic T cells.@@@@1@20@@oe@16-12-2010 1035225806@GENIA Treebank@formal@@1@S@The proliferative deficiency of the transgenic T cells was associated with an increased apoptosis.@@@@1@15@@oe@16-12-2010 1035225807@GENIA Treebank@formal@@1@S@These results point out the involvement of NF-kappa B/Rel family proteins in growth signaling pathways by either regulating proteins involved in the IL-2 signaling or by functionally interfering with the cell cycle progression.@@@@1@34@@oe@16-12-2010 1035227301@GENIA Treebank@formal@@1@S@Modulation of CD28 expression: distinct regulatory pathways during activation and replicative senescence.@@@@1@14@@oe@16-12-2010 1035227302@GENIA Treebank@formal@@1@S@The costimulatory molecule CD28 has a restricted tissue distribution and is expressed on T cells and some plasmacytoma cells.@@@@1@20@@oe@16-12-2010 1035227303@GENIA Treebank@formal@@1@S@Although CD28 is constitutively expressed, its expression is transiently down-regulated following T cell activation and declines progressively with in vitro senescence.@@@@1@23@@oe@16-12-2010 1035227304@GENIA Treebank@formal@@1@S@In vivo, CD8+ T cells and, less frequently, CD4+ T cells may completely lose CD28 surface expression during chronic infections and with aging.@@@@1@27@@oe@16-12-2010 1035227305@GENIA Treebank@formal@@1@S@This correlates with changes of nuclear protein-binding activities to two motifs, site alpha and beta, within the CD28 minimal promoter.@@@@1@23@@oe@16-12-2010 1035227306@GENIA Treebank@formal@@1@S@Both alpha- and beta-bound complexes are found only in lymphoid tissues, in CD28+ T cells, and in some transformed B cells.@@@@1@24@@oe@16-12-2010 1035227307@GENIA Treebank@formal@@1@S@These complexes are coordinately expressed except during replicative senescence, which is characterized by the down-modulation of site beta- but not site alpha-binding activities.@@@@1@25@@oe@16-12-2010 1035227308@GENIA Treebank@formal@@1@S@In contrast, T cell activation induces a parallel decline in both site alpha- and beta-binding activities.@@@@1@18@@oe@16-12-2010 1035227309@GENIA Treebank@formal@@1@S@CD4+ and CD8+ T cells differ in their beta-binding profiles, which may explain the more pronounced down-regulation of CD28 in senescent CD8+ T cells.@@@@1@26@@oe@16-12-2010 1035227310@GENIA Treebank@formal@@1@S@In vivo expanded CD4+CD28null and CD8+CD28null T cells uniformly lack alpha- and beta- bound complexes, resembling the pattern seen in chronically activated cells and not of senescent cells.@@@@1@29@@oe@16-12-2010 1035227901@GENIA Treebank@formal@@1@S@CD28 costimulation augments IL-2 secretion of activated lamina propria T cells by increasing mRNA stability without enhancing IL-2 gene transactivation.@@@@1@21@@oe@16-12-2010 1035227902@GENIA Treebank@formal@@1@S@The pathways leading to activation in lamina propria (LP) T cells are different from peripheral T cells.@@@@1@20@@oe@16-12-2010 1035227903@GENIA Treebank@formal@@1@S@LP T cells exhibit enhanced IL-2 secretion when activated through the CD2 pathway.@@@@1@14@@oe@16-12-2010 1035227904@GENIA Treebank@formal@@1@S@Coligation of CD28 leads to synergistic enhancement of IL-2 secretion.@@@@1@11@@oe@16-12-2010 1035227905@GENIA Treebank@formal@@1@S@Previous studies have characterized the CD28 augmentation of TCR-mediated signaling in peripheral blood T cells through transcriptional activation of an IL-2 promoter CD28 response element (CD28RE), along with enhanced mRNA stability.@@@@1@35@@oe@16-12-2010 1035227906@GENIA Treebank@formal@@1@S@This study characterized molecular events involved in CD28 costimulation of IL-2 production in LP mononuclear cells (LPMC).@@@@1@20@@oe@16-12-2010 1035227907@GENIA Treebank@formal@@1@S@LPMC exhibited increased IL-2 production in response to CD28 costimulation, compared with cells activated through CD2 alone.@@@@1@19@@oe@16-12-2010 1035227908@GENIA Treebank@formal@@1@S@IL-2 secretion was paralleled by increased expression of IL-2 mRNA, resulting from enhanced IL-2 mRNA stability.@@@@1@18@@oe@16-12-2010 1035227909@GENIA Treebank@formal@@1@S@In contrast to transcriptional activation in PBMC, EMSA revealed that CD28 coligation of CD2-activated LPMC does not result in increased binding of trans-factors to the CD28RE, nor did Western blots detect changes in I-kappaBalpha or I-kappaBbeta levels following CD28 coligation.@@@@1@43@@oe@16-12-2010 1035227910@GENIA Treebank@formal@@1@S@Furthermore, CD28 coligation fails to enhance IL-2 promoter-reporter or RE/AP construct expression in CD2-activated LPMC.@@@@1@17@@oe@16-12-2010 1035227911@GENIA Treebank@formal@@1@S@The results reported herein indicate that the molecular mechanisms involved in CD28 cosignaling and regulation of IL-2 secretion in LP T cells are unique to that compartment and differ from those seen in peripheral blood T cells.@@@@1@38@@oe@16-12-2010 1035227912@GENIA Treebank@formal@@1@S@These observations suggest a biological significance for different mechanisms of IL-2 activation in initiation and maintenance of the cytokine repertoire found in the mucosa.@@@@1@25@@oe@16-12-2010 1035662901@GENIA Treebank@formal@@1@S@Glucocorticoid receptors in anorexia nervosa and Cushing's disease.@@@@1@10@@oe@16-12-2010 1035662902@GENIA Treebank@formal@@1@S@BACKGROUND: Patients with anorexia nervosa do not display cushingoid features in spite of elevated cortisol plasma levels.@@@@1@19@@oe@16-12-2010 1035662903@GENIA Treebank@formal@@1@S@Whether a cortisol resistance or a reduced availability of the metabolic substrates necessary to develop the effect of glucocorticoids is responsible for this has not been established.@@@@1@28@@oe@16-12-2010 1035662904@GENIA Treebank@formal@@1@S@METHODS: Twenty-two patients with severe restrictive anorexia nervosa, 10 patients with active Cushing's disease, and 24 healthy volunteers without psychiatric disorders or mood alterations were investigated.@@@@1@31@@oe@16-12-2010 1035662905@GENIA Treebank@formal@@1@S@Glucocorticoid receptor characteristics were examined on mononuclear leukocytes by measuring [3H]dexamethasone binding and the effect of dexamethasone on [3H]thymidine incorporation, which represents an index of DNA synthesis.@@@@1@29@@oe@16-12-2010 1035662906@GENIA Treebank@formal@@1@S@RESULTS: The number of glucocorticoid receptors on mononuclear leukocytes (MNL) was comparable in patients with anorexia nervosa, patients with active Cushing's disease, and normal subjects (binding capacity 3.3 +/- 0.23 vs. 3.7 +/- 0.30 and 3.5 +/- 0.20 fmol/10(6) cells).@@@@1@49@@oe@16-12-2010 1035662907@GENIA Treebank@formal@@1@S@Conversely, glucocorticoid receptor affinity was significantly decreased in anorexia nervosa as well as in Cushing's patients compared to control subjects (dissociation constant 4.0 +/- 0.31 and 4.1 +/- 0.34 vs. 2.9 +/- 0.29 nmol/L, p < .001) and inversely correlated with the levels of urinary free cortisol in both groups of patients.@@@@1@58@@oe@16-12-2010 1035662908@GENIA Treebank@formal@@1@S@Basal [3H]thymidine incorporation in MNL was significantly reduced in anorexia nervosa as well as in Cushing's patients compared to control subjects (p < .001) and was diminished by dexamethasone to an extent similar to control subjects in patients with anorexia nervosa, but significantly (p < .001) less in those with Cushing's disease.@@@@1@60@@oe@16-12-2010 1035662909@GENIA Treebank@formal@@1@S@In patients with anorexia nervosa, the incorporation of [3H]thymidine into the MNL was inversely correlated with urinary free cortisol levels.@@@@1@22@@oe@16-12-2010 1035662910@GENIA Treebank@formal@@1@S@CONCLUSIONS: These data indicate that the lack of cushingoid features in patients with anorexia nervosa is not ascribable to a reduced sensitivity to glucocorticoids but is more likely due to the paucity of metabolic substrates.@@@@1@37@@oe@16-12-2010 1035781801@GENIA Treebank@formal@@1@S@Latent membrane protein 1 of Epstein-Barr virus interacts with JAK3 and activates STAT proteins.@@@@1@15@@oe@16-12-2010 1035781802@GENIA Treebank@formal@@1@S@Latent membrane protein 1 (LMP1) acts like a permanently activated receptor of the tumor necrosis factor (TNF)-receptor superfamily and is absolutely required for B cell immortalization by Epstein-Barr virus.@@@@1@35@@oe@16-12-2010 1035781803@GENIA Treebank@formal@@1@S@Molecular and biochemical approaches demonstrated that LMP1 usurps cellular signaling pathways resulting in the induction of NF-kappaB and AP-1 via two C-terminal activating regions.@@@@1@25@@oe@16-12-2010 1035781804@GENIA Treebank@formal@@1@S@We demonstrate here that a third region encompassing a proline rich sequence within the 33 bp repetitive stretch of LMP1's C-terminus is required for the activation of Janus kinase 3 (JAK3).@@@@1@35@@oe@16-12-2010 1035781805@GENIA Treebank@formal@@1@S@The interaction of LMP1 and JAK3 leads to the enhanced tyrosine auto/transphosphorylation of JAK3 within minutes after crosslinking of a conditional NGF-R:LMP1 chimera and is a prerequisite for the activation of STAT transcription factors.@@@@1@35@@oe@16-12-2010 1035781806@GENIA Treebank@formal@@1@S@These results reveal a novel activating region in the LMP1 C-terminus and identify the JAK/STAT pathway as a target of this viral integral membrane protein in B cells.@@@@1@29@@oe@16-12-2010 1035782001@GENIA Treebank@formal@@1@S@Repression by Ikaros and Aiolos is mediated through histone deacetylase complexes.@@@@1@12@@oe@16-12-2010 1035782002@GENIA Treebank@formal@@1@S@Here we show that the lymphoid lineage-determining factors Ikaros and Aiolos can function as strong transcriptional repressors.@@@@1@18@@oe@16-12-2010 1035782003@GENIA Treebank@formal@@1@S@This function is mediated through two repression domains and is dependent upon the promoter context and cell type.@@@@1@19@@oe@16-12-2010 1035782004@GENIA Treebank@formal@@1@S@Repression by Ikaros proteins correlates with hypo-acetylation of core histones at promoter sites and is relieved by histone deacetylase inhibitors.@@@@1@21@@oe@16-12-2010 1035782005@GENIA Treebank@formal@@1@S@Consistent with these findings, Ikaros and its repression domains can interact in vivo and in vitro with the mSin3 family of co-repressors which bind to histone deacetylases.@@@@1@29@@oe@16-12-2010 1035782006@GENIA Treebank@formal@@1@S@Based on these and our recent findings of associations between Ikaros and Mi-2-HDAC, we propose that Ikaros family members modulate gene expression during lymphocyte development by recruiting distinct histone deacetylase complexes to specific promoters.@@@@1@36@@oe@16-12-2010 1035802801@GENIA Treebank@formal@@1@S@20-Epi analogues of 1,25-dihydroxyvitamin D3 are highly potent inducers of DRIP coactivator complex binding to the vitamin D3 receptor.@@@@1@20@@oe@16-12-2010 1035802802@GENIA Treebank@formal@@1@S@1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) plays a major role in the stimulation of bone growth, mineralization, and intestinal calcium and phosphate absorption; it also acts as a general inhibitor of cellular proliferation.@@@@1@36@@oe@16-12-2010 1035802803@GENIA Treebank@formal@@1@S@Several new, clinically relevant compounds dissociate antiproliferative and calcemic activities of 1,25(OH)2D3, but the molecular basis for this has not been clearly elucidated.@@@@1@26@@oe@16-12-2010 1035802804@GENIA Treebank@formal@@1@S@Here, we tested whether the potency of one class of compounds, 20-epi analogues, to induce myeloid cell differentiation, is because of direct molecular effects on vitamin D receptor (VDR).@@@@1@36@@oe@16-12-2010 1035802805@GENIA Treebank@formal@@1@S@We report that two 20-epi analogues, MC1627 and MC1288, induced differentiation and transcription of p21(Waf1,Cip1), a key VDR target gene involved in growth inhibition, at a concentration 100-fold lower than that of 1,25(OH)2D3.@@@@1@43@@oe@16-12-2010 1035802806@GENIA Treebank@formal@@1@S@We compared this sensitivity to analogue effects on VDR interacting proteins: RXR, GRIP-1, and DRIP205, a subunit of the DRIP coactivator complex.@@@@1@27@@oe@16-12-2010 1035802807@GENIA Treebank@formal@@1@S@Compared with the interaction of VDR with RXR or GRIP-1, the differentiation dose-response most closely correlated to the ligand-dependent recruitment of the DRIP coactivator complex to VDR and to the ability of the receptor to activate transcription in a cell-free system.@@@@1@43@@oe@16-12-2010 1035802808@GENIA Treebank@formal@@1@S@These results provide compelling links between the efficiency of the 20-epi analogue in inducing VDR/DRIP interactions, transactivation in vitro, and its enhanced ability to induce cellular differentiation.@@@@1@30@@oe@16-12-2010 1035815401@GENIA Treebank@formal@@1@S@New immunosuppressive drug PNU156804 blocks IL-2-dependent proliferation and NF-kappa B and AP-1 activation.@@@@1@14@@oe@16-12-2010 1035815402@GENIA Treebank@formal@@1@S@We had previously shown that the drug undecylprodigiosin (UP) blocks human lymphocyte proliferation in vitro.@@@@1@18@@oe@16-12-2010 1035815403@GENIA Treebank@formal@@1@S@We have now investigated the mechanism of action of a new analogue of UP, PNU156804, which shows a more favorable activity profile than UP in mice.@@@@1@29@@oe@16-12-2010 1035815404@GENIA Treebank@formal@@1@S@We demonstrate here that the biological effect of PNU156804 in vitro is indistinguishable from UP: PNU156804 blocks human T cell proliferation in mid-late G1, as determined by cell cycle analysis, expression of cyclins, and cyclin-dependent kinases and retinoblastoma phosphorylation.@@@@1@44@@oe@16-12-2010 1035815405@GENIA Treebank@formal@@1@S@In addition, we show that PNU156804 does not block significantly the induction of either IL-2 or IL-2R alpha- and gamma-chains but inhibits IL-2-dependent T cell proliferation.@@@@1@28@@oe@16-12-2010 1035815406@GENIA Treebank@formal@@1@S@We have investigated several molecular pathways that are known to be activated by IL-2 in T cells.@@@@1@18@@oe@16-12-2010 1035815407@GENIA Treebank@formal@@1@S@We show that PNU156804 does not inhibit c-myc and bcl-2 mRNA induction.@@@@1@13@@oe@16-12-2010 1035815408@GENIA Treebank@formal@@1@S@On the other hand, PNU156804 efficiently inhibits the activation of the NF-kappa B and AP-1 transcription factors.@@@@1@19@@oe@16-12-2010 1035815409@GENIA Treebank@formal@@1@S@PNU156804 inhibition of NF-kappa B activation is due to the inhibition of the degradation of I kappa B-alpha and I kappa B-beta.@@@@1@23@@oe@16-12-2010 1035815410@GENIA Treebank@formal@@1@S@PNU156804 action is restricted to some signaling pathways; it does not affect NF-kappa B activation by PMA in T cells but blocks that induced by CD40 cross-linking in B lymphocytes.@@@@1@32@@oe@16-12-2010 1035815411@GENIA Treebank@formal@@1@S@We conclude that the prodigiosin family of immunosuppressants is a new family of molecules that show a novel target specificity clearly distinct from that of other immunosuppressive drugs such as cyclosporin A, FK506, and rapamycin.@@@@1@38@@oe@16-12-2010 1035817301@GENIA Treebank@formal@@1@S@IL-12 induces IFN regulating factor-1 (IRF-1) gene expression in human NK and T cells.@@@@1@17@@oe@16-12-2010 1035817302@GENIA Treebank@formal@@1@S@IL-12 is a critical immunoregulatory cytokine that promotes cell-mediated immune responses and the differentiation of naive CD4+ cells to Th1 cells; however, relatively few IL-12 target genes have been identified.@@@@1@33@@oe@16-12-2010 1035817303@GENIA Treebank@formal@@1@S@To better clarify the molecular basis of IL-12 action, we set out to characterize genes up-regulated by IL-12, first by contrasting IL-12- and IFN-alpha-inducible genes.@@@@1@28@@oe@16-12-2010 1035817304@GENIA Treebank@formal@@1@S@We identified several genes up-regulated by IL-12, namely, MIP-1alpha, MIP-1beta, IL-1RA, and IFN regulatory factor-1 (IRF-1).@@@@1@24@@oe@16-12-2010 1035817305@GENIA Treebank@formal@@1@S@IRF-1 is a transcription factor regulated by IFNs that is also essential for Th1 responses.@@@@1@16@@oe@16-12-2010 1035817306@GENIA Treebank@formal@@1@S@We demonstrated that IL-12 directly up-regulates IRF-1 to the same extent as IFN-alpha in normal human T cells and in NK cells.@@@@1@23@@oe@16-12-2010 1035817307@GENIA Treebank@formal@@1@S@We showed that IL-12 had a direct effect on IRF-1, an effect not mediated indirectly by the induction of IFN-gamma production.@@@@1@23@@oe@16-12-2010 1035817308@GENIA Treebank@formal@@1@S@Furthermore, IL-2 and IL-12 synergistically induced IRF-1, whereas IFN-alpha and IL-12 did not.@@@@1@16@@oe@16-12-2010 1035817309@GENIA Treebank@formal@@1@S@The participation of STAT4 in the regulation of IRF-1 was demonstrated in two ways.@@@@1@15@@oe@16-12-2010 1035817310@GENIA Treebank@formal@@1@S@First, STAT4 was required for the IL-12-dependent transactivation of an IRF-1 reporter construct, and second, STAT4 binding to the IRF-1 promoter was shown using EMSA.@@@@1@29@@oe@16-12-2010 1035817311@GENIA Treebank@formal@@1@S@In contrast to IL-12, no up-regulation of IRF-1 was found in IL-4-stimulated cells, and IL-4 did not block IL-12-dependent up-regulation of IRF-1.@@@@1@25@@oe@16-12-2010 1035817312@GENIA Treebank@formal@@1@S@Therefore, IRF-1 may be an important contributor to IL-12 signaling, and we speculate that the defective IL-12 responses seen in IRF-1-/- mice might be attributable, in part, to the absence of this transcription factor.@@@@1@39@@oe@16-12-2010 1035817801@GENIA Treebank@formal@@1@S@Multiple NF-ATc isoforms with individual transcriptional properties are synthesized in T lymphocytes.@@@@1@13@@oe@16-12-2010 1035817802@GENIA Treebank@formal@@1@S@The transcription factor NF-ATc that controls gene expression in T lymphocytes and embryonic cardiac cells is expressed in three prominent isoforms.@@@@1@22@@oe@16-12-2010 1035817803@GENIA Treebank@formal@@1@S@This is due to alternative splice/polyadenylation events that lead to the predominant synthesis of two long isoforms in naive T cells and a shorter NF-ATc isoform in effector T cells.@@@@1@31@@oe@16-12-2010 1035817804@GENIA Treebank@formal@@1@S@Whereas the previously described isoform NF-ATc/A contains a relatively short C terminus, the longer isoforms, B and C, span extra C-terminal peptides of 128 and 246 aa, respectively.@@@@1@33@@oe@16-12-2010 1035817805@GENIA Treebank@formal@@1@S@We show here that in addition to the strong N-terminal trans-activation domain, TAD-A, which is common to all three NF-ATc isoforms, NF-ATc/C contains a second trans-activation domain, TAD-B, in its C-terminal peptide.@@@@1@38@@oe@16-12-2010 1035817806@GENIA Treebank@formal@@1@S@Various stimuli of T cells that induce the activity of TAD-A also enhance the activity of TAD-B, but, unlike TAD-A, TAD-B remains unphosphorylated by protein from 12-O-tetradecanoyl 12-phorbol 13-acetate-stimulated T cells.@@@@1@35@@oe@16-12-2010 1035817807@GENIA Treebank@formal@@1@S@The shorter C-terminal peptide of isoform NF-ATc/B exerts a suppressive transcriptional effect.@@@@1@13@@oe@16-12-2010 1035817808@GENIA Treebank@formal@@1@S@These properties of NF-ATc/B and- C might be of importance for gene regulation in naive T lymphocytes in which NF-ATc/B and -C are predominantly synthesized.@@@@1@26@@oe@16-12-2010 1035875601@GENIA Treebank@formal@@1@S@Transcriptional regulation of T lymphocyte development and function.@@@@1@9@@oe@16-12-2010 1035875602@GENIA Treebank@formal@@1@S@The development and function of T lymphocytes are regulated tightly by signal transduction pathways that include specific cell-surface receptors, intracellular signaling molecules, and nuclear transcription factors.@@@@1@29@@oe@16-12-2010 1035875603@GENIA Treebank@formal@@1@S@Since 1988, several families of functionally important T cell transcription factors have been identified.@@@@1@16@@oe@16-12-2010 1035875604@GENIA Treebank@formal@@1@S@These include the Ikaros, LKLF, and GATA3 zinc-finger proteins; the Ets, CREB/ATF, and NF-kappa B/Rel/NFAT transcription factors; the Stat proteins; and HMG box transcription factors such as LEF1, TCF1, and Sox4.@@@@1@41@@oe@16-12-2010 1035875605@GENIA Treebank@formal@@1@S@In this review, we summarize our current understanding of the transcriptional regulation of T cell development and function with particular emphasis on the results of recent gene targeting and transgenic experiments.@@@@1@33@@oe@16-12-2010 1035875606@GENIA Treebank@formal@@1@S@In addition to increasing our understanding of the molecular pathways that regulate T cell development and function, these results have suggested novel targets for genetic and pharmacological manipulation of T cell immunity.@@@@1@34@@oe@16-12-2010 1035876401@GENIA Treebank@formal@@1@S@Development and maturation of secondary lymphoid tissues.@@@@1@8@@oe@16-12-2010 1035876402@GENIA Treebank@formal@@1@S@The secondary lymphoid tissues are located at strategic sites where foreign antigens can be efficiently brought together with immune system regulatory and effector cells.@@@@1@25@@oe@16-12-2010 1035876403@GENIA Treebank@formal@@1@S@The organized structure of the secondary lymphoid tissues is thought to enhance the sensitivity of antigen recognition and to support proper regulation of the activation and maturation of the antigen-responsive lymphoid cells.@@@@1@33@@oe@16-12-2010 1035876404@GENIA Treebank@formal@@1@S@Although a substantial amount is known about the cellular elements that compose the lymphoid and nonlymphoid components of the secondary lymphoid tissues, information concerning the signals that control the development of the tissues and that maintain the organized tissue microenvironment remain undefined.@@@@1@44@@oe@16-12-2010 1035876405@GENIA Treebank@formal@@1@S@Studies over the past few years have identified lymphotoxin as a critical signaling molecule not only for the organogenesis of secondary lymphoid tissues but for the maintenance of aspects of their microarchitecture as well.@@@@1@35@@oe@16-12-2010 1035876406@GENIA Treebank@formal@@1@S@Additional signaling molecules that contribute to the formation of normal lymphoid tissue structure are being identified at an accelerating pace.@@@@1@21@@oe@16-12-2010 1035876407@GENIA Treebank@formal@@1@S@Analyses of mouse strains with congenital defects in different aspects of secondary lymphoid tissue development are beginning to clarify the role of these tissues in immune responses and host defense.@@@@1@31@@oe@16-12-2010 1035876408@GENIA Treebank@formal@@1@S@This review focuses on studies defining recently identified crucial signals for the biogenesis of secondary lymphoid organs and for the maintenance of their proper microarchitecture.@@@@1@26@@oe@16-12-2010 1035876409@GENIA Treebank@formal@@1@S@It also discusses new insights into how the structure of these tissues supports effective immune responses.@@@@1@17@@oe@16-12-2010 1035877501@GENIA Treebank@formal@@1@S@Selection of the T cell repertoire.@@@@1@7@@oe@16-12-2010 1035877502@GENIA Treebank@formal@@1@S@Advances in gene technology have allowed the manipulation of molecular interactions that shape the T cell repertoire.@@@@1@18@@oe@16-12-2010 1035877503@GENIA Treebank@formal@@1@S@Although recognized as fundamental aspects of T lymphocyte development, only recently have the mechanisms governing positive and negative selection been examined at a molecular level.@@@@1@27@@oe@16-12-2010 1035877504@GENIA Treebank@formal@@1@S@Positive selection refers to the active process of rescuing MHC-restricted thymocytes from programmed cell death.@@@@1@16@@oe@16-12-2010 1035877505@GENIA Treebank@formal@@1@S@Negative selection refers to the deletion or inactivation of potentially autoreactive thymocytes.@@@@1@13@@oe@16-12-2010 1035877506@GENIA Treebank@formal@@1@S@This review focuses on interactions during thymocyte maturation that define the T cell repertoire, with an emphasis placed on current literature within this field.@@@@1@26@@oe@16-12-2010 1035901201@GENIA Treebank@formal@@1@S@Phorbol ester-induced mononuclear cell differentiation is blocked by the mitogen-activated protein kinase kinase (MEK) inhibitor PD98059.@@@@1@19@@oe@16-12-2010 1035901202@GENIA Treebank@formal@@1@S@The purpose of this study was to evaluate whether the mitogen-activated protein kinase (MAPK) signaling pathway contributes to 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mononuclear differentiation in the human myeloblastic leukemia ML-1 cells.@@@@1@35@@oe@16-12-2010 1035901203@GENIA Treebank@formal@@1@S@Upon TPA treatment, the activity of ERK1 and ERK2 rapidly increased, with maximal induction between 1 and 3 h, while ERK2 protein levels remained constant.@@@@1@29@@oe@16-12-2010 1035901204@GENIA Treebank@formal@@1@S@The activity of JNK1 was also significantly induced, with JNK1 protein levels increasing moderately during exposure to TPA.@@@@1@20@@oe@16-12-2010 1035901205@GENIA Treebank@formal@@1@S@Treatment of cells with PD98059, a specific inhibitor of mitogen-activated protein kinase kinase (MEK), inhibited TPA-induced ERK2 activity.@@@@1@23@@oe@16-12-2010 1035901206@GENIA Treebank@formal@@1@S@Furthermore, PD98059 completely blocked the TPA-induced differentiation of ML-1 cells, as assessed by a number of features associated with mononuclear differentiation including changes in morphology, nonspecific esterase activity, phagocytic ability, NADPH oxidase activity, mitochondrial respiration, and c-jun mRNA inducibility.@@@@1@47@@oe@16-12-2010 1035901207@GENIA Treebank@formal@@1@S@We conclude that activation of the MEK/ERK signaling pathway is necessary for TPA-induced mononuclear cell differentiation.@@@@1@17@@oe@16-12-2010 1035913801@GENIA Treebank@formal@@1@S@Immune functions, clinical parameters and hormone receptor status in breast cancer patients.@@@@1@14@@oe@16-12-2010 1035913802@GENIA Treebank@formal@@1@S@We have carried out a detailed analysis of the cellular immune functions of breast cancer patients in comparison with healthy controls.@@@@1@22@@oe@16-12-2010 1035913803@GENIA Treebank@formal@@1@S@A possible correlation between immune and clinical parameters was analysed in 50 breast cancer patients.@@@@1@16@@oe@16-12-2010 1035913804@GENIA Treebank@formal@@1@S@Immune parameters, natural killer cell and T lymphocyte functions and the numbers of circulating T lymphocytes were analysed against the clinical parameters comprising the tumour burden, the stage of the disease and the expression of hormone receptors on the tumour.@@@@1@43@@oe@16-12-2010 1035913805@GENIA Treebank@formal@@1@S@In order to analyse the immune function data effectively, low responders were identified with stringent cut-off values.@@@@1@19@@oe@16-12-2010 1035913806@GENIA Treebank@formal@@1@S@Considerably higher proportions of low responders were found among the patient population.@@@@1@13@@oe@16-12-2010 1035913807@GENIA Treebank@formal@@1@S@Elevated numbers of circulating T lymphocytes and CD3-directed cytolysis correlated with the expression of oestrogen receptors independently of the clinical/histological parameters.@@@@1@22@@oe@16-12-2010 1035945701@GENIA Treebank@formal@@1@S@UV-induced CYP1A1 gene expression in human cells is mediated by tryptophan.@@@@1@12@@oe@16-12-2010 1035945702@GENIA Treebank@formal@@1@S@Induction of cytochrome P-4501A1 (CYP1A1) activity by UV has been observed earlier in animal studies via a mechanism that has not yet been resolved.@@@@1@27@@oe@16-12-2010 1035945703@GENIA Treebank@formal@@1@S@Our previous data have indicated that formylated indolocarbazoles which are formed by UV irradiation of tryptophan solutions are very potent Ah-receptor agonists.@@@@1@23@@oe@16-12-2010 1035945704@GENIA Treebank@formal@@1@S@To evaluate the effect of UV light on cytochrome P4501A1 gene expression, we studied the induction of CYP1A1 mRNA by UV irradiation of cultured human keratinocytes (HaCaT cell line), primary human blood lymphocytes and mouse Hepa-1 cells.@@@@1@42@@oe@16-12-2010 1035945705@GENIA Treebank@formal@@1@S@The cells were exposed to UV light delivered by a bank of 6 Philips TL20/12RS sun lamps emitting primarily in the UVB range in the absence and presence of tryptophan.@@@@1@31@@oe@16-12-2010 1035945706@GENIA Treebank@formal@@1@S@A semiquantitative reverse transcriptase-linked polymerase chain reaction (RT-PCR) was used for analysis of gene expression in the treated cells.@@@@1@22@@oe@16-12-2010 1035945707@GENIA Treebank@formal@@1@S@The results show that the CYP1A1 mRNA level induced by UV in the presence of tryptophan was higher than that induced by UV alone in both HaCaT cells and lymphocytes after 3 h of incubation post-UV irradiation.@@@@1@38@@oe@16-12-2010 1035945708@GENIA Treebank@formal@@1@S@To find out if the induction by UV light is caused by the formation of an Ah receptor ligand, Hepa-1 wild-type and Ah receptor deficient c12 cell lines were applied.@@@@1@32@@oe@16-12-2010 1035945709@GENIA Treebank@formal@@1@S@Wild-type (wt) cells were inducible either by the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole (FICZ) or by UV-irradiation but very low or undetectable levels were observed in the c12 cells.@@@@1@38@@oe@16-12-2010 1035945710@GENIA Treebank@formal@@1@S@This shows that the induction of gene expression by FICZ and UV is Ah receptor dependent.@@@@1@17@@oe@16-12-2010 1035945711@GENIA Treebank@formal@@1@S@Together, these results indicate that UV-induced CYP1A1 gene expression in mammalian cells is mediated by an Ah receptor ligand formed from tryptophan.@@@@1@24@@oe@16-12-2010 1035945712@GENIA Treebank@formal@@1@S@Thus, the photoproducts of tryptophan are suggested to be mediators of light via binding to the Ah receptor and as such also could have a role in light-regulated biological rhythms.@@@@1@32@@oe@16-12-2010 1035989401@GENIA Treebank@formal@@1@S@Effects of diesel organic extracts on chemokine production by peripheral blood mononuclear cells.@@@@1@14@@oe@16-12-2010 1035989402@GENIA Treebank@formal@@1@S@BACKGROUND: Polyaromatic hydrocarbons (PAHs) associated with diesel exhaust particles (DEPs) are found in the atmospheric urban pollution.@@@@1@23@@oe@16-12-2010 1035989403@GENIA Treebank@formal@@1@S@Such compounds have been shown to favor IgE production, bronchial hyperresponsiveness, and airway inflammation.@@@@1@17@@oe@16-12-2010 1035989404@GENIA Treebank@formal@@1@S@Chemokines are a group of chemotactic cytokines involved in the recruitment of inflammatory cells.@@@@1@15@@oe@16-12-2010 1035989405@GENIA Treebank@formal@@1@S@OBJECTIVE: We investigated the effect of DEP-PAHs on the release and mRNA expression of IL-8, MCP-1, and RANTES by PBMCs obtained from healthy subjects.@@@@1@28@@oe@16-12-2010 1035989406@GENIA Treebank@formal@@1@S@METHODS: Protein production in supernatants was assessed by ELISA, and mRNA expression was evaluated by semiquantitative RT-PCR.@@@@1@20@@oe@16-12-2010 1035989407@GENIA Treebank@formal@@1@S@RESULTS: Secretion of IL-8 and RANTES increased in a dose-dependent manner with increasing concentrations of DEP-PAHs (range, 0.5 ng to 50 ng/mL).@@@@1@27@@oe@16-12-2010 1035989408@GENIA Treebank@formal@@1@S@On the contrary, the release of MCP-1 was significantly inhibited, also in a dose-dependent manner.@@@@1@18@@oe@16-12-2010 1035989409@GENIA Treebank@formal@@1@S@Messenger RNA production coding for IL-8, RANTES, and MCP-1 showed parallel variations to the production of the correspondent proteins.@@@@1@22@@oe@16-12-2010 1035989410@GENIA Treebank@formal@@1@S@Effects of DEP-PAHs became significant at 7 hours and up to 48 hours time culture for MCP-1, and up to 24 hours time culture for IL-8 and RANTES.@@@@1@30@@oe@16-12-2010 1035989411@GENIA Treebank@formal@@1@S@Moreover, supernatants from DEP-PAH-activated cells, compared with those of controls, exhibited a significantly enhanced chemotactic activity for neutrophils and eosinophils, which was significantly inhibited by pretreatment with anti-IL-8 and anti-RANTES neutralizing antibodies, respectively.@@@@1@39@@oe@16-12-2010 1035989412@GENIA Treebank@formal@@1@S@CONCLUSION: These findings suggest that the chemokine pathways are modulated by DEP-PAHs at the transcriptional level, reinforcing the idea that the development of inflammatory reactions might be affected by diesel exhaust emission.@@@@1@35@@oe@16-12-2010 1035989501@GENIA Treebank@formal@@1@S@Binding of YY1 and Oct1 to a novel element that downregulates expression of IL-5 in human T cells.@@@@1@19@@oe@16-12-2010 1035989502@GENIA Treebank@formal@@1@S@BACKGROUND: IL-5 controls development of eosinophilia and has been shown to be involved in the pathogenesis of allergic diseases.@@@@1@21@@oe@16-12-2010 1035989503@GENIA Treebank@formal@@1@S@In both atopic and nonatopic asthma, elevated IL-5 has been detected in peripheral blood and the airways.@@@@1@19@@oe@16-12-2010 1035989504@GENIA Treebank@formal@@1@S@IL-5 is produced mainly by activated T cells, and its expression is regulated at the transcriptional level.@@@@1@19@@oe@16-12-2010 1035989505@GENIA Treebank@formal@@1@S@OBJECTIVE: This study focuses on the functional analysis of the human IL-5 (hIL-5) promoter and characterization of cis -regulatory elements and transcription factors involved in the suppression of IL-5 transcription in T cells.@@@@1@36@@oe@16-12-2010 1035989506@GENIA Treebank@formal@@1@S@METHODS: Methods used in this study include DNase I footprint assays, electrophoretic mobility shift assays, and functional analysis by mammalian cell transfection involving deletion analysis and site-directed mutagenesis.@@@@1@32@@oe@16-12-2010 1035989507@GENIA Treebank@formal@@1@S@RESULTS: We identified 5 protein binding regions (BRs) located within the proximal hIL-5 promoter.@@@@1@18@@oe@16-12-2010 1035989508@GENIA Treebank@formal@@1@S@Functional analysis indicates that the BRs are involved in control of hIL-5 promoter activity.@@@@1@15@@oe@16-12-2010 1035989509@GENIA Treebank@formal@@1@S@Two of these regions, BR3 and BR4 located at positions -102 to -73, have not previously been described as regulators of IL-5 expression in T cells.@@@@1@29@@oe@16-12-2010 1035989510@GENIA Treebank@formal@@1@S@We show that the BR3 sequence contains a novel negative regulatory element located at positions -90 to -79 of the hIL-5 promoter, which binds Oct1, octamer-like, and YY1 nuclear factors.@@@@1@34@@oe@16-12-2010 1035989511@GENIA Treebank@formal@@1@S@Substitution mutations, which abolished binding of these proteins to the BR3 sequence, significantly increased hIL-5 promoter activity in activated T cells.@@@@1@24@@oe@16-12-2010 1035989512@GENIA Treebank@formal@@1@S@CONCLUSION: We suggest that Oct1, YY1, and octamer-like factors binding to the -90/-79 sequence within the proximal IL-5 promoter are involved in suppression of IL-5 transcription in T cells.@@@@1@33@@oe@16-12-2010 1036415701@GENIA Treebank@formal@@1@S@Direct interaction of hematopoietic transcription factors PU.1 and GATA-1: functional antagonism in erythroid cells.@@@@1@16@@oe@16-12-2010 1036415702@GENIA Treebank@formal@@1@S@Malignant transformation usually inhibits terminal cell differentiation but the precise mechanisms involved are not understood.@@@@1@16@@oe@16-12-2010 1036415703@GENIA Treebank@formal@@1@S@PU.1 is a hematopoietic-specific Ets family transcription factor that is required for development of some lymphoid and myeloid lineages.@@@@1@20@@oe@16-12-2010 1036415704@GENIA Treebank@formal@@1@S@PU.1 can also act as an oncoprotein as activation of its expression in erythroid precursors by proviral insertion or transgenesis causes erythroleukemias in mice.@@@@1@25@@oe@16-12-2010 1036415705@GENIA Treebank@formal@@1@S@Restoration of terminal differentiation in the mouse erythroleukemia (MEL) cells requires a decline in the level of PU.1, indicating that PU.1 can block erythroid differentiation.@@@@1@29@@oe@16-12-2010 1036415706@GENIA Treebank@formal@@1@S@Here we investigate the mechanism by which PU.1 interferes with erythroid differentiation.@@@@1@13@@oe@16-12-2010 1036415707@GENIA Treebank@formal@@1@S@We find that PU.1 interacts directly with GATA-1, a zinc finger transcription factor required for erythroid differentiation.@@@@1@19@@oe@16-12-2010 1036415708@GENIA Treebank@formal@@1@S@Interaction between PU.1 and GATA-1 requires intact DNA-binding domains in both proteins.@@@@1@13@@oe@16-12-2010 1036415709@GENIA Treebank@formal@@1@S@PU.1 represses GATA-1-mediated transcriptional activation.@@@@1@6@@oe@16-12-2010 1036415710@GENIA Treebank@formal@@1@S@Both the DNA binding and transactivation domains of PU.1 are required for repression and both domains are also needed to block terminal differentiation in MEL cells.@@@@1@27@@oe@16-12-2010 1036415711@GENIA Treebank@formal@@1@S@We also show that ectopic expression of PU.1 in Xenopus embryos is sufficient to block erythropoiesis during normal development.@@@@1@20@@oe@16-12-2010 1036415712@GENIA Treebank@formal@@1@S@Furthermore, introduction of exogenous GATA-1 in both MEL cells and Xenopus embryos and explants relieves the block to erythroid differentiation imposed by PU.1.@@@@1@25@@oe@16-12-2010 1036415713@GENIA Treebank@formal@@1@S@Our results indicate that the stoichiometry of directly interacting but opposing transcription factors may be a crucial determinant governing processes of normal differentiation and malignant transformation.@@@@1@27@@oe@16-12-2010 1036419101@GENIA Treebank@formal@@1@S@Potent and stable attenuation of live-HIV-1 by gain of a proteolysis-resistant inhibitor of NF-kappaB (IkappaB-alphaS32/36A) and the implications for vaccine development.@@@@1@24@@oe@16-12-2010 1036419102@GENIA Treebank@formal@@1@S@Live-attenuated human immunodeficiency viruses (HIVs) are candidates for Acquired Immunodeficiency Syndrome (AIDS) vaccine.@@@@1@18@@oe@16-12-2010 1036419103@GENIA Treebank@formal@@1@S@Based on the simian immunodeficiency virus (SIV) model for AIDS, loss-of-function (e.g. deletion of accessory genes such as nef) has been forwarded as a primary approach for creating enfeebled, but replication-competent, HIV-1/SIV.@@@@1@40@@oe@16-12-2010 1036419104@GENIA Treebank@formal@@1@S@Regrettably, recent evidence suggests that loss-of-function alone is not always sufficient to prevent the emergence of virulent mutants.@@@@1@20@@oe@16-12-2010 1036419105@GENIA Treebank@formal@@1@S@New strategies that attenuate via mechanisms distinct from loss-of-function are needed for enhancing the safety phenotype of viral genome.@@@@1@20@@oe@16-12-2010 1036419106@GENIA Treebank@formal@@1@S@Here, we propose gain-of-function to be used simultaneously with loss-of-function as a novel approach for attenuating HIV-1.@@@@1@19@@oe@16-12-2010 1036419107@GENIA Treebank@formal@@1@S@We have constructed an HIV-1 genome carrying the cDNA of a proteolysis-resistant nuclear factor-kappaB inhibitor (IkappaB-alphaS32/36A) in the nef region.@@@@1@23@@oe@16-12-2010 1036419108@GENIA Treebank@formal@@1@S@HIV-1 expressing IkappaB-alphaS32/36A down-regulates viral expression and is highly attenuated in both Jurkat and peripheral blood mononuclear cells.@@@@1@19@@oe@16-12-2010 1036419109@GENIA Treebank@formal@@1@S@We provide formal proof that the phenotypic and attenuating characteristics of IkappaB-alphaS32/36A permit its stable maintenance in a live, replicating HIV-1 despite 180 days of forced ex vivo passaging in tissue culture.@@@@1@34@@oe@16-12-2010 1036419110@GENIA Treebank@formal@@1@S@As compared with other open-reading frames embedded into HIV/SIV genome, this degree of stability is unprecedented.@@@@1@18@@oe@16-12-2010 1036419111@GENIA Treebank@formal@@1@S@Thus, IkappaB-alphaS32/36A offers proof-of-principle that artifactually gained functions, when used to attenuate the replication of live HIV-1, can be stable.@@@@1@24@@oe@16-12-2010 1036419112@GENIA Treebank@formal@@1@S@These findings illustrate gain-of-function as a feasible strategy for developing safer live-attenuated HIVs to be tested as candidates for AIDS vaccine.@@@@1@22@@oe@16-12-2010 1036419301@GENIA Treebank@formal@@1@S@Oxidative stress triggers STAT3 tyrosine phosphorylation and nuclear translocation in human lymphocytes.@@@@1@13@@oe@16-12-2010 1036419302@GENIA Treebank@formal@@1@S@Oxidizing agents are powerful activators of factors responsible for the transcriptional activation of cytokine-encoding genes involved in tissue injury.@@@@1@20@@oe@16-12-2010 1036419303@GENIA Treebank@formal@@1@S@In this study we show evidence that STAT3 is a transcription factor whose activity is modulated by H2O2 in human lymphocytes, in which endogenous catalase had previously been inhibited.@@@@1@31@@oe@16-12-2010 1036419304@GENIA Treebank@formal@@1@S@H2O2-induced nuclear translocation of STAT3 to form sequence-specific DNA-bound complexes was evidenced by immunoblotting of nuclear fractions and electrophoretic mobility shift assays, and vanadate was found to strongly synergize with H2O2.@@@@1@33@@oe@16-12-2010 1036419305@GENIA Treebank@formal@@1@S@Moreover, anti-STAT3 antibodies specifically precipitated a protein of 92 kDa that becomes phosphorylated on tyrosine upon lymphocyte treatment with H2O2.@@@@1@22@@oe@16-12-2010 1036419306@GENIA Treebank@formal@@1@S@Phenylarsine oxide, a tyrosine phosphatase inhibitor, and genistein, a tyrosine kinase inhibitor, cooperated and cancelled, respectively, the H2O2-promoted STAT3 nuclear translocation.@@@@1@28@@oe@16-12-2010 1036419307@GENIA Treebank@formal@@1@S@Evidence is also presented, using Fe2+/Cu2+ ions, that.OH generated from H2O2 through Fenton reactions could be a candidate oxygen reactive species to directly activate STAT3.@@@@1@29@@oe@16-12-2010 1036419308@GENIA Treebank@formal@@1@S@Present data suggest that H2O2 and vanadate are likely to inhibit the activity of intracellular tyrosine phosphatase(s), leading to enhanced STAT3 tyrosine phosphorylation and hence its translocation to the nucleus.@@@@1@35@@oe@16-12-2010 1036419309@GENIA Treebank@formal@@1@S@These results demonstrate that the DNA binding activity of STAT3 can be modulated by oxidizing agents and provide a framework to understand the effects of oxidative stress on the JAK-STAT signaling pathway.@@@@1@33@@oe@16-12-2010 1036426001@GENIA Treebank@formal@@1@S@Human alveolar macrophages are markedly deficient in REF-1 and AP-1 DNA binding activity.@@@@1@14@@oe@16-12-2010 1036426002@GENIA Treebank@formal@@1@S@Although many functions of human alveolar macrophages are altered compared with their precursor cell, the blood monocyte (monocyte), the reason(s) for these functional changes have not been determined.@@@@1@36@@oe@16-12-2010 1036426003@GENIA Treebank@formal@@1@S@We recently reported that human alveolar macrophages do not express AP-1 DNA binding activity (Monick, M. M., Carter, A. B., Gudmundsson, G., Geist, L. J., and Hunninghake, G. W. (1998) Am. J. Physiol. 275, L389-L397).@@@@1@50@@oe@16-12-2010 1036426004@GENIA Treebank@formal@@1@S@To determine why alveolar macrophages do not express AP-1 DNA binding activity, we first showed that there was not a decrease in expression of the FOS and JUN proteins that make up the AP-1 complex.@@@@1@37@@oe@16-12-2010 1036426005@GENIA Treebank@formal@@1@S@There was, however, a significant difference in the amounts of the nuclear protein, REF-1 (which regulates AP-1 DNA binding by altering the redox status of FOS and JUN proteins), in alveolar macrophages compared with monocytes.@@@@1@42@@oe@16-12-2010 1036426006@GENIA Treebank@formal@@1@S@In addition, in vitro differentiation of monocytes to a macrophage-like cell resulted in decreased amounts of REF-1.@@@@1@19@@oe@16-12-2010 1036426007@GENIA Treebank@formal@@1@S@Finally, addition of REF-1 from activated monocytes to alveolar macrophage nuclear proteins resulted in a marked increase in AP-1 DNA binding.@@@@1@23@@oe@16-12-2010 1036426008@GENIA Treebank@formal@@1@S@These studies strongly suggest that the process of differentiation of monocytes into alveolar macrophages is associated with a loss of REF-1 and AP-1 activity.@@@@1@25@@oe@16-12-2010 1036426009@GENIA Treebank@formal@@1@S@This observation may explain, in part, some of the functional differences observed for alveolar macrophages compared with monocytes.@@@@1@21@@oe@16-12-2010 1036660001@GENIA Treebank@formal@@1@S@Monocyte adhesion and spreading on human endothelial cells is dependent on Rho-regulated receptor clustering.@@@@1@15@@oe@16-12-2010 1036660002@GENIA Treebank@formal@@1@S@The GTPase Rho is known to mediate the assembly of integrin-containing focal adhesions and actin stress fibers.@@@@1@18@@oe@16-12-2010 1036660003@GENIA Treebank@formal@@1@S@Here, we investigate the role of Rho in regulating the distribution of the monocyte-binding receptors E-selectin, ICAM-1, and VCAM-1 in human endothelial cells.@@@@1@27@@oe@16-12-2010 1036660004@GENIA Treebank@formal@@1@S@Inhibition of Rho activity with C3 transferase or N19RhoA, a dominant negative RhoA mutant, reduced the adhesion of monocytes to activated endothelial cells and inhibited their spreading.@@@@1@30@@oe@16-12-2010 1036660005@GENIA Treebank@formal@@1@S@Similar effects were observed after pretreatment of endothelial cells with cytochalasin D.@@@@1@13@@oe@16-12-2010 1036660006@GENIA Treebank@formal@@1@S@In contrast, dominant negative Rac and Cdc42 proteins did not affect monocyte adhesion or spreading.@@@@1@17@@oe@16-12-2010 1036660007@GENIA Treebank@formal@@1@S@C3 transferase and cytochalasin D did not alter the expression levels of monocyte-binding receptors on endothelial cells, but did inhibit clustering of E-selectin, ICAM-1, and VCAM-1 on the cell surface induced by monocyte adhesion or cross-linking antibodies.@@@@1@41@@oe@16-12-2010 1036660008@GENIA Treebank@formal@@1@S@Similarly, N19RhoA inhibited receptor clustering.@@@@1@7@@oe@16-12-2010 1036660009@GENIA Treebank@formal@@1@S@Monocyte adhesion and receptor cross-linking induced stress fiber assembly, and inhibitors of myosin light chain kinase prevented this response but did not affect receptor clustering.@@@@1@27@@oe@16-12-2010 1036660010@GENIA Treebank@formal@@1@S@Finally, receptor clusters colocalized with ezrin/moesin/radixin proteins.@@@@1@9@@oe@16-12-2010 1036660011@GENIA Treebank@formal@@1@S@These results suggest that Rho is required in endothelial cells for the assembly of stable adhesions with monocytes via the clustering of monocyte-binding receptors and their association with the actin cytoskeleton, independent of stress fiber formation.@@@@1@38@@oe@16-12-2010 1036769801@GENIA Treebank@formal@@1@S@Binding characteristics of the glucocorticoid receptor in peripheral blood lymphocytes in multiple sclerosis.@@@@1@14@@oe@16-12-2010 1036769802@GENIA Treebank@formal@@1@S@Although the exact etiology of multiple sclerosis (MS) remains unresolved, immune reactions are believed to be the central pathogenic mechanisms.@@@@1@24@@oe@16-12-2010 1036769803@GENIA Treebank@formal@@1@S@Endogenous and therapeutic steroid hormones affect the immune system, and inflammatory diseases are associated with activation of the hypothalamic-pituitary-adrenal axis, providing evidence of an immune-endocrine interplay.@@@@1@29@@oe@16-12-2010 1036769804@GENIA Treebank@formal@@1@S@Function tests in MS have revealed dysregulation of the hypothalamic-pituitary-adrenal system in a substantial proportion of patients.@@@@1@18@@oe@16-12-2010 1036769805@GENIA Treebank@formal@@1@S@We characterized glucocorticoid receptor (GR) binding in peripheral blood lymphocytes from 39 MS patients and 14 age- and sex-matched controls with respect to dissociation constant and binding capacity, using a whole-cell binding assay with [3H]dexamethasone as the ligand.@@@@1@42@@oe@16-12-2010 1036769806@GENIA Treebank@formal@@1@S@GR binding parameters did not differ significantly between patients (Kd 8.98 +/- 1.07 nM, Bmax 183 +/- 29.8 fmol/mg) and controls (Kd 9.36 +/- 1.17 nM, Bmax 158 +/- 16 fmol/mg).@@@@1@38@@oe@16-12-2010 1036769807@GENIA Treebank@formal@@1@S@No effect of age, sex, course, duration or severity of disease, or prior steroid treatments was detected.@@@@1@22@@oe@16-12-2010 1036769808@GENIA Treebank@formal@@1@S@GR binding parameters were analyzed in relation to the results of the combined dexamethasone-CRH test, which reflects corticosteroid receptor function at the hypothalamus, in 30 patients and 9 controls.@@@@1@32@@oe@16-12-2010 1036769809@GENIA Treebank@formal@@1@S@While controls showed a moderate correlation between binding affinity of the GR in lymphocytes and regulatory function at the hypothalamic level, the patients did not.@@@@1@27@@oe@16-12-2010 1036769810@GENIA Treebank@formal@@1@S@These data suggest that the physiological relationship between binding and function of the glucocorticoid receptor is disturbed in MS.@@@@1@20@@oe@16-12-2010 1036789701@GENIA Treebank@formal@@1@S@CBP/p300 integrates Raf/Rac-signaling pathways in the transcriptional induction of NF-ATc during T cell activation.@@@@1@15@@oe@16-12-2010 1036789702@GENIA Treebank@formal@@1@S@NF-ATc, an inducibly expressed transcription factor, controls gene expression in T lymphocytes and cardiomyocytes.@@@@1@17@@oe@16-12-2010 1036789703@GENIA Treebank@formal@@1@S@We show here that the transcriptional co-activators CBP/p300 bind to and control the activity of the inducible N-terminal transactivation domain of NF-ATc, TAD-A.@@@@1@25@@oe@16-12-2010 1036789704@GENIA Treebank@formal@@1@S@Similar to the N terminal transactivation domain of c-Jun, TAD-A is inducibly phosphorylated, but this phosphorylation is dispensable for the interaction with CBP/p300.@@@@1@26@@oe@16-12-2010 1036789705@GENIA Treebank@formal@@1@S@Constitutive active versions of c-Raf and Rac synergistically enhance the CBP/p300-mediated increase of TAD-A activity, indicating the important role CBP/p300 plays in the integration of T cell activation signals.@@@@1@31@@oe@16-12-2010 1036789706@GENIA Treebank@formal@@1@S@Since a mutation of CBP abolishing HAT activity is almost as active as wild-type CBP in T cells, functions of CBP/p300 other than histone acetylation appear to control the NF-AT-dependent transcription in T cells.@@@@1@36@@oe@16-12-2010 1036925501@GENIA Treebank@formal@@1@S@A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria [see comments]@@@@1@20@@oe@16-12-2010 1036925502@GENIA Treebank@formal@@1@S@Genetic variation in cytokine promoter regions is postulated to influence susceptibility to infection, but the molecular mechanisms by which such polymorphisms might affect gene regulation are unknown.@@@@1@29@@oe@16-12-2010 1036925503@GENIA Treebank@formal@@1@S@Through systematic DNA footprinting of the TNF (encoding tumour necrosis factor, TNF) promoter region, we have identified a single nucleotide polymorphism (SNP) that causes the helix-turn-helix transcription factor OCT-1 to bind to a novel region of complex protein-DNA interactions and alters gene expression in human monocytes.@@@@1@53@@oe@16-12-2010 1036925504@GENIA Treebank@formal@@1@S@The OCT-1-binding genotype, found in approximately 5% of Africans, is associated with fourfold increased susceptibility to cerebral malaria in large case-control studies of West African and East African populations, after correction for other known TNF polymorphisms and linked HLA alleles.@@@@1@45@@oe@16-12-2010 1036941901@GENIA Treebank@formal@@1@S@Association of the interleukin-4 receptor alpha chain with p47phox, an activator of the phagocyte NADPH oxidase in B cells.@@@@1@21@@oe@16-12-2010 1036941902@GENIA Treebank@formal@@1@S@Interleukin (IL)-4 plays an important role in IgE synthesis in B cells and in Th2 differentiation in T cells.@@@@1@23@@oe@16-12-2010 1036941903@GENIA Treebank@formal@@1@S@IL-4 conducts its biological activities through binding to the IL-4 receptor (IL-4R) on the surface of target cells.@@@@1@21@@oe@16-12-2010 1036941904@GENIA Treebank@formal@@1@S@IL-4R are thought to be composed of the IL-4R alpha chain (IL-4R alpha) and either the IL-2R gamma chain or the IL-13R alpha chain.@@@@1@27@@oe@16-12-2010 1036941905@GENIA Treebank@formal@@1@S@We have previously shown that the membrane-proximal portion in the cytoplasmic domain of the human IL-4R alpha (hIL-4R alpha) is critical for proliferation, generation of germline epsilon transcript, and activation of STAT6, based on analyses of truncated hIL-4R alphas.@@@@1@45@@oe@16-12-2010 1036941906@GENIA Treebank@formal@@1@S@In this study, we found that p47phox, an activator of the phagocyte NADPH oxidase, binds to this portion by the two-hybrid system.@@@@1@26@@oe@16-12-2010 1036941907@GENIA Treebank@formal@@1@S@Furthermore, we observed the association of p47phox with the hIL-4R alpha in B cells derived from a normal donor.@@@@1@21@@oe@16-12-2010 1036941908@GENIA Treebank@formal@@1@S@These results suggest that p47phox is involved in the signal transduction of IL-4 in B cells.@@@@1@17@@oe@16-12-2010 1036941909@GENIA Treebank@formal@@1@S@However, activation of STAT6, CD23 expression, and IgE synthesis induced by IL-4 were not affected in p47phox-deficient patients, which raises the possibility that p47phox may be important in other signaling activities as well in B cells.@@@@1@41@@oe@16-12-2010 1036968101@GENIA Treebank@formal@@1@S@Aiolos transcription factor controls cell death in T cells by regulating Bcl-2 expression and its cellular localization.@@@@1@18@@oe@16-12-2010 1036968102@GENIA Treebank@formal@@1@S@We searched for proteins that interact with Ras in interleukin (IL)-2-stimulated or IL-2-deprived cells, and found that the transcription factor Aiolos interacts with Ras.@@@@1@29@@oe@16-12-2010 1036968103@GENIA Treebank@formal@@1@S@The Ras-Aiolos interaction was confirmed in vitro and in vivo by co-immunoprecipitation.@@@@1@13@@oe@16-12-2010 1036968104@GENIA Treebank@formal@@1@S@Indirect immunofluorescence shows that IL-2 controls the cellular distribution of Aiolos and induces its tyrosine phosphorylation, required for dissociation from Ras.@@@@1@23@@oe@16-12-2010 1036968105@GENIA Treebank@formal@@1@S@We also identified functional Aiolos-binding sites in the Bcl-2 promoter, which are able to activate the luciferase reporter gene.@@@@1@21@@oe@16-12-2010 1036968106@GENIA Treebank@formal@@1@S@Mutation of Aiolos-binding sites within the Bcl-2 promoter inhibits transactivation of the reporter gene luciferase, suggesting direct control of Bcl-2 expression by Aiolos.@@@@1@25@@oe@16-12-2010 1036968107@GENIA Treebank@formal@@1@S@Co-transfection experiments confirm that Aiolos induces Bcl-2 expression and prevents apoptosis in IL-2-deprived cells.@@@@1@15@@oe@16-12-2010 1036968108@GENIA Treebank@formal@@1@S@We propose a model for the regulation of Bcl-2 expression via Aiolos.@@@@1@13@@oe@16-12-2010 1037037201@GENIA Treebank@formal@@1@S@C/EBP beta in rheumatoid arthritis: correlation with inflammation, not disease specificity.@@@@1@14@@oe@16-12-2010 1037037202@GENIA Treebank@formal@@1@S@Rheumatoid arthritis synovial tissue was examined and compared with osteoarthritis tissue for the presence of the nuclear transcription factor C/EBP beta (NF-IL-6).@@@@1@25@@oe@16-12-2010 1037037203@GENIA Treebank@formal@@1@S@The region (lining or sublining), cell type, and subcellular distribution (cytoplasmic or nuclear) of the expression of C/EBP beta was characterized.@@@@1@28@@oe@16-12-2010 1037037204@GENIA Treebank@formal@@1@S@Rheumatoid arthritis synovial fluid and blood and normal peripheral blood were also examined.@@@@1@14@@oe@16-12-2010 1037037205@GENIA Treebank@formal@@1@S@C/EBP beta was detected in the synovial lining and in sublining cells of synovial tissue from patients with both rheumatoid and osteoarthritis.@@@@1@23@@oe@16-12-2010 1037037206@GENIA Treebank@formal@@1@S@A significant (P < 0.001 and < 0.05, respectively) increase in the percentage of cells with nuclear staining was seen in the lining layer, compared to cells in the sublining region, in rheumatoid and osteoarthritis.@@@@1@41@@oe@16-12-2010 1037037207@GENIA Treebank@formal@@1@S@In both diseases a strong correlation (r = 0.79, P < 0.001) was observed between the percentage of cells in the synovial lining that were positive for nuclear C/EBP beta and lining cell depth.@@@@1@38@@oe@16-12-2010 1037037208@GENIA Treebank@formal@@1@S@Two-color immunohistochemistry demonstrated that both macrophages and fibroblast-like synoviocytes were positive for nuclear C/EBP beta.@@@@1@16@@oe@16-12-2010 1037037209@GENIA Treebank@formal@@1@S@The presence of C/EBP beta was confirmed by immunohistochemistry and Western blot analysis with isolated synovial fibroblasts.@@@@1@18@@oe@16-12-2010 1037037210@GENIA Treebank@formal@@1@S@Nuclear C/EBP beta was also detected in rheumatoid synovial fluid monocytes/macrophages, but not in lymphocytes or neutrophils.@@@@1@19@@oe@16-12-2010 1037037211@GENIA Treebank@formal@@1@S@Western blot analysis confirmed the presence of C/EBP beta in these cells.@@@@1@13@@oe@16-12-2010 1037037212@GENIA Treebank@formal@@1@S@The intensity of C/EBP beta staining was greater (P < 0.001) in synovial fluid monocytes than in those from normal or rheumatoid peripheral blood.@@@@1@27@@oe@16-12-2010 1037037213@GENIA Treebank@formal@@1@S@In conclusion, the enhanced nuclear staining for C/EBP beta in the synovial lining, compared to the sublining, suggesting activation in the lining, and the positive correlation of lining layer depth with the percentage of cells in the lining positive for nuclear C/EBP beta, suggest a potential role for C/EBP beta in chronic inflammation.@@@@1@59@@oe@16-12-2010 1037037214@GENIA Treebank@formal@@1@S@The regulation of the production or activity of C/EBP beta, to inhibit inflammatory mediator expression by synovial macrophages and fibroblasts, offers a novel approach to therapeutic intervention.@@@@1@30@@oe@16-12-2010 1037227101@GENIA Treebank@formal@@1@S@Novel therapies for inflammatory bowel disease.@@@@1@7@@oe@16-12-2010 1037227102@GENIA Treebank@formal@@1@S@Looking back at successes and failures in newer approaches to treating IBD, it is tempting--although still difficult--to draw conclusions about pathogenesis.@@@@1@27@@oe@16-12-2010 1037227103@GENIA Treebank@formal@@1@S@When a therapy proves effective, do clinicians truly know how it works?@@@@1@14@@oe@16-12-2010 1037227104@GENIA Treebank@formal@@1@S@Even with a therapy as specific as anti-TNF antibody, it is not clear if the benefit is attributable to simple binding and clearance of TNF-alpha or to binding on the cell surface and subsequent deletion of the activated macrophage.@@@@1@41@@oe@16-12-2010 1037227105@GENIA Treebank@formal@@1@S@When a drug appears to be less effective than preclinical models suggest, can failures in effectiveness from delivery or dosing be differentiated?@@@@1@24@@oe@16-12-2010 1037227106@GENIA Treebank@formal@@1@S@The disappointing results of clinical trials with IL-10--so at odds with the prediction of benefit from animal models--bring into question the validity of those models as well as the soundness of design of the clinical trials on which efficacy of IL-10 is judged.@@@@1@48@@oe@16-12-2010 1037227107@GENIA Treebank@formal@@1@S@The variability of response even to the most narrowly targeted agents suggests that these diseases are far more heterogeneous in humans than in their murine counterparts.@@@@1@27@@oe@16-12-2010 1037227108@GENIA Treebank@formal@@1@S@Clinicians are only just beginning to recognize subclinical markers of response, and it may soon be possible to predict response on the basis of genetic composition.@@@@1@28@@oe@16-12-2010 1037227109@GENIA Treebank@formal@@1@S@For the moment, however, the field of pharmacogenetics is embryonic.@@@@1@13@@oe@16-12-2010 1037227110@GENIA Treebank@formal@@1@S@Challenges in developing new therapeutic strategies include not only identifying novel agents, but also improving the definitions of clinical endpoints and defining efficacy at the biologic level.@@@@1@29@@oe@16-12-2010 1037227111@GENIA Treebank@formal@@1@S@Only through considered evaluation of clinical evidence may clinicians determine which therapies should remain novelties and which should become an accepted part of the armamentarium.@@@@1@26@@oe@16-12-2010 1037352201@GENIA Treebank@formal@@1@S@p70(s6k) integrates phosphatidylinositol 3-kinase and rapamycin-regulated signals for E2F regulation in T lymphocytes.@@@@1@14@@oe@16-12-2010 1037352202@GENIA Treebank@formal@@1@S@In T lymphocytes, the hematopoietic cytokine interleukin-2 (IL-2) uses phosphatidylinositol 3-kinase (PI 3-kinase)-induced signaling pathways to regulate E2F transcriptional activity, a critical cell cycle checkpoint.@@@@1@33@@oe@16-12-2010 1037352203@GENIA Treebank@formal@@1@S@PI 3-kinase also regulates the activity of p70(s6k), the 40S ribosomal protein S6 kinase, a response that is abrogated by the macrolide rapamycin.@@@@1@26@@oe@16-12-2010 1037352204@GENIA Treebank@formal@@1@S@This immunosuppressive drug is known to prevent T-cell proliferation, but the precise point at which rapamycin regulates T-cell cycle progression has yet to be elucidated.@@@@1@27@@oe@16-12-2010 1037352205@GENIA Treebank@formal@@1@S@Moreover, the effects of rapamycin on, and the role of p70(s6k) in, IL-2 and PI 3-kinase activation of E2Fs have not been characterized.@@@@1@27@@oe@16-12-2010 1037352206@GENIA Treebank@formal@@1@S@Our present results show that IL-2- and PI 3-kinase-induced pathways for the regulation of E2F transcriptional activity include both rapamycin-resistant and rapamycin-sensitive components.@@@@1@24@@oe@16-12-2010 1037352207@GENIA Treebank@formal@@1@S@Expression of a rapamycin-resistant mutant of p70(s6k) in T cells could restore rapamycin-suppressed E2F responses.@@@@1@16@@oe@16-12-2010 1037352208@GENIA Treebank@formal@@1@S@Thus, the rapamycin-controlled processes involved in E2F regulation appear to be mediated by p70(s6k).@@@@1@16@@oe@16-12-2010 1037352209@GENIA Treebank@formal@@1@S@However, the rapamycin-resistant p70(s6k) could not rescue rapamycin inhibition of T-cell cycle entry, consistent with the involvement of additional, rapamycin-sensitive pathways in the control of T-cell cycle progression.@@@@1@32@@oe@16-12-2010 1037352210@GENIA Treebank@formal@@1@S@The present results thus show that p70(s6k) is able to regulate E2F transcriptional activity and provide direct evidence for the first time for a link between IL-2 receptors, PI 3-kinase, and p70(s6k) that regulates a crucial G1 checkpoint in T lymphocytes.@@@@1@44@@oe@16-12-2010 1037354801@GENIA Treebank@formal@@1@S@SOCS-3 is tyrosine phosphorylated in response to interleukin-2 and suppresses STAT5 phosphorylation and lymphocyte proliferation.@@@@1@16@@oe@16-12-2010 1037354802@GENIA Treebank@formal@@1@S@Members of the recently discovered SOCS/CIS/SSI family have been proposed as regulators of cytokine signaling, and while targets and mechanisms have been suggested for some family members, the precise role of these proteins remains to be defined.@@@@1@40@@oe@16-12-2010 1037354803@GENIA Treebank@formal@@1@S@To date no SOCS proteins have been specifically implicated in interleukin-2 (IL-2) signaling in T cells.@@@@1@19@@oe@16-12-2010 1037354804@GENIA Treebank@formal@@1@S@Here we report SOCS-3 expression in response to IL-2 in both T-cell lines and human peripheral blood lymphocytes.@@@@1@19@@oe@16-12-2010 1037354805@GENIA Treebank@formal@@1@S@SOCS-3 protein was detectable as early as 30 min following IL-2 stimulation, while CIS was seen only at low levels after 2 h.@@@@1@25@@oe@16-12-2010 1037354806@GENIA Treebank@formal@@1@S@Unlike CIS, SOCS-3 was rapidly tyrosine phosphorylated in response to IL-2.@@@@1@13@@oe@16-12-2010 1037354807@GENIA Treebank@formal@@1@S@Tyrosine phosphorylation of SOCS-3 was observed upon coexpression with Jak1 and Jak2 but only weakly with Jak3.@@@@1@18@@oe@16-12-2010 1037354808@GENIA Treebank@formal@@1@S@In these experiments, SOCS-3 associated with Jak1 and inhibited Jak1 phosphorylation, and this inhibition was markedly enhanced by the presence of IL-2 receptor beta chain (IL-2Rbeta).@@@@1@31@@oe@16-12-2010 1037354809@GENIA Treebank@formal@@1@S@Moreover, following IL-2 stimulation of T cells, SOCS-3 was able to interact with the IL-2 receptor complex, and in particular tyrosine phosphorylated Jak1 and IL-2Rbeta.@@@@1@29@@oe@16-12-2010 1037354810@GENIA Treebank@formal@@1@S@Additionally, in lymphocytes expressing SOCS-3 but not CIS, IL-2-induced tyrosine phosphorylation of STAT5b was markedly reduced, while there was only a weak effect on IL-3-mediated STAT5b tyrosine phosphorylation.@@@@1@32@@oe@16-12-2010 1037354811@GENIA Treebank@formal@@1@S@Finally, proliferation induced by both IL-2- and IL-3 was significantly inhibited in the presence of SOCS-3.@@@@1@18@@oe@16-12-2010 1037354812@GENIA Treebank@formal@@1@S@The findings suggest that when SOCS-3 is rapidly induced by IL-2 in T cells, it acts to inhibit IL-2 responses in a classical negative feedback loop.@@@@1@28@@oe@16-12-2010 1037469901@GENIA Treebank@formal@@1@S@The role of gamma/delta T cell receptor positive cells in pregnancy.@@@@1@12@@oe@16-12-2010 1037469902@GENIA Treebank@formal@@1@S@PROBLEM: Due to the lack of classical HLA antigens on the trophoblast, fetal antigens are possibly presented in a non major histocompatibility complex (MHC) restricted way.@@@@1@31@@oe@16-12-2010 1037469903@GENIA Treebank@formal@@1@S@Decidual gammadelta T cells, which significantly increase in number during pregnancy, might play a role in recognition of fetal antigens and also in determining the quality of the response to these antigens.@@@@1@35@@oe@16-12-2010 1037469904@GENIA Treebank@formal@@1@S@Our study was aimed at investigating the role of this cell population in progesterone-dependent immunomodulation.@@@@1@16@@oe@16-12-2010 1037469905@GENIA Treebank@formal@@1@S@METHOD OF STUDY: Peripheral lymphocytes from healthy pregnant women and from habitual aborters were tested by immunocytochemistry for the presence of gamma/delta T cell receptor (TCR) and progesterone receptor.@@@@1@33@@oe@16-12-2010 1037469906@GENIA Treebank@formal@@1@S@To investigate the effect of treatment with a pan anti gamma/delta antibody, lymphocytes were incubated for 3 hr with the antibody, and then interleukin (IL)-10, IL-12 and progesterone-induced blocking factor (PIBF) expression (by immuno-cytochemistry) as well as natural killer (NK) cell activity were determined.@@@@1@57@@oe@16-12-2010 1037469907@GENIA Treebank@formal@@1@S@RESULTS: In peripheral blood of healthy pregnant women the percentage of gamma/delta TCR+ cells was significantly higher (P < 0.001) than in that of recurrent aborters or of non-pregnant individuals.@@@@1@34@@oe@16-12-2010 1037469908@GENIA Treebank@formal@@1@S@Ninety-seven percent of gamma/delta TCR+ pregnancy lymphocytes expressed progesterone receptor.@@@@1@11@@oe@16-12-2010 1037469909@GENIA Treebank@formal@@1@S@Binding of a specific antibody to the gamma/delta TCR inhibited PIBF- as well as IL-10 production, whereas it increased NK activity and IL-12 expression.@@@@1@26@@oe@16-12-2010 1037469910@GENIA Treebank@formal@@1@S@CONCLUSIONS: These data suggest the role of gamma/delta TCR-bearing lymphocytes in progesterone-dependent immunomodulation.@@@@1@15@@oe@16-12-2010 1037653101@GENIA Treebank@formal@@1@S@Expression and role of PML gene in normal adult hematopoiesis: functional interaction between PML and Rb proteins in erythropoiesis.@@@@1@21@@oe@16-12-2010 1037653102@GENIA Treebank@formal@@1@S@The expression of the PML gene was investigated in purified early hematopoietic progenitor cells (HPCs) induced to unilineage erythroid or granulocytic differentiation.@@@@1@25@@oe@16-12-2010 1037653103@GENIA Treebank@formal@@1@S@PML mRNA and protein, while barely detectable in quiescent HPCs, are consistently induced by growth factor stimulation through the erythroid or granulocytic lineage.@@@@1@26@@oe@16-12-2010 1037653104@GENIA Treebank@formal@@1@S@Thereafter, PML is downmodulated in late granulocytic maturation, whereas it is sustainably expressed through the erythroid pathway.@@@@1@20@@oe@16-12-2010 1037653105@GENIA Treebank@formal@@1@S@In functional studies, PML expression was inhibited by addition of antisense oligomers targeting PML mRNA (alpha-PML).@@@@1@20@@oe@16-12-2010 1037653106@GENIA Treebank@formal@@1@S@Interestingly, early treatment (day 0 HPCs) with alpha-PML reduced the number of both erythroid and granulocytic colonies, whereas late treatment (day 5 culture) reduced erythroid, but not granulocytic, clonogenesis.@@@@1@38@@oe@16-12-2010 1037653107@GENIA Treebank@formal@@1@S@These findings suggest that PML is required for early hematopoiesis and erythroid, but not granulocytic maturation.@@@@1@18@@oe@16-12-2010 1037653108@GENIA Treebank@formal@@1@S@The pattern of PML expression in normal hematopoiesis mimics that of retinoblastoma pRb 105.@@@@1@15@@oe@16-12-2010 1037653109@GENIA Treebank@formal@@1@S@Combined treatment of HPCs with alpha-PML and alpha-Rb oligomers inhibited both PML and Rb protein expression and completely blocked erythroid colony development.@@@@1@23@@oe@16-12-2010 1037653110@GENIA Treebank@formal@@1@S@Furthermore, PML and pRb 105 were co-immunoprecipitated in cellular lysates derived from erythroid precursors indicating that this functional interaction may have a biochemical basis.@@@@1@26@@oe@16-12-2010 1037653111@GENIA Treebank@formal@@1@S@These results suggest a key functional role of PML in early hematopoiesis and late erythropoiesis: the latter phenomenon may be related to the molecular and functional interaction of PML with pRb 105.@@@@1@34@@oe@16-12-2010 1037707501@GENIA Treebank@formal@@1@S@PPARalpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells.@@@@1@14@@oe@16-12-2010 1037707502@GENIA Treebank@formal@@1@S@BACKGROUND: Adhesion molecule expression on the endothelial cell (EC) surface is critical for leukocyte recruitment to atherosclerotic lesions.@@@@1@22@@oe@16-12-2010 1037707503@GENIA Treebank@formal@@1@S@Better understanding of transcriptional regulation of adhesion molecules in ECs may provide important insight into plaque formation.@@@@1@18@@oe@16-12-2010 1037707504@GENIA Treebank@formal@@1@S@Peroxisome proliferator-activated receptor-alpha (PPARalpha), a member of the nuclear receptor family, regulates gene expression in response to certain fatty acids and fibric acid derivatives.@@@@1@29@@oe@16-12-2010 1037707505@GENIA Treebank@formal@@1@S@The present study investigated PPARalpha expression in human ECs and their regulation of vascular cell adhesion molecule-1 (VCAM-1).@@@@1@21@@oe@16-12-2010 1037707506@GENIA Treebank@formal@@1@S@METHODS AND RESULTS: Immunohistochemistry revealed that human carotid artery ECs express PPARalpha.@@@@1@14@@oe@16-12-2010 1037707507@GENIA Treebank@formal@@1@S@Pretreatment of cultured human ECs with the PPARalpha activators fenofibrate or WY14643 inhibited TNF-alpha-induced VCAM-1 in a time- and concentration-dependent manner, an effect not seen with PPARgamma activators.@@@@1@30@@oe@16-12-2010 1037707508@GENIA Treebank@formal@@1@S@Both PPARalpha activators decreased cytokine-induced VCAM-1 mRNA expression without altering its mRNA half-life.@@@@1@14@@oe@16-12-2010 1037707509@GENIA Treebank@formal@@1@S@Transient transfection of deletional VCAM-1 promoter constructs and electrophoretic mobility shift assays suggest that fenofibrate inhibits VCAM-1 transcription in part by inhibiting NF-kappaB.@@@@1@24@@oe@16-12-2010 1037707510@GENIA Treebank@formal@@1@S@Finally, PPARalpha activators significantly reduced adhesion of U937 cells to cultured human ECs.@@@@1@15@@oe@16-12-2010 1037707511@GENIA Treebank@formal@@1@S@CONCLUSIONS: Human ECs express PPARalpha, a potentially important regulator of atherogenesis through its transcriptional control of VCAM-1 gene expression.@@@@1@22@@oe@16-12-2010 1037707512@GENIA Treebank@formal@@1@S@Such findings also have implications regarding the clinical use of lipid-lowering agents, like fibric acids, which can activate PPARalpha.@@@@1@22@@oe@16-12-2010 1037741101@GENIA Treebank@formal@@1@S@The intracellular parasite Theileria parva protects infected T cells from apoptosis.@@@@1@12@@oe@16-12-2010 1037741102@GENIA Treebank@formal@@1@S@Parasites have evolved a plethora of strategies to ensure their survival.@@@@1@12@@oe@16-12-2010 1037741103@GENIA Treebank@formal@@1@S@The intracellular parasite Theileria parva secures its propagation and spreads through the infected animal by infecting and transforming T cells, inducing their continuous proliferation and rendering them metastatic.@@@@1@30@@oe@16-12-2010 1037741104@GENIA Treebank@formal@@1@S@In previous work, we have shown that the parasite induces constitutive activation of the transcription factor NF-kappaB, by inducing the constitutive degradation of its cytoplasmic inhibitors.@@@@1@29@@oe@16-12-2010 1037741105@GENIA Treebank@formal@@1@S@The biological significance of NF-kappaB activation in T. parva-infected cells, however, has not yet been defined.@@@@1@19@@oe@16-12-2010 1037741106@GENIA Treebank@formal@@1@S@Cells that have been transformed by viruses or oncogenes can persist only if they manage to avoid destruction by the apoptotic mechanisms that are activated on transformation and that contribute to maintain cellular homeostasis.@@@@1@35@@oe@16-12-2010 1037741107@GENIA Treebank@formal@@1@S@We now demonstrate that parasite-induced NF-kappaB activation plays a crucial role in the survival of T. parva-transformed T cells by conveying protection against an apoptotic signal that accompanies parasite-mediated transformation.@@@@1@31@@oe@16-12-2010 1037741108@GENIA Treebank@formal@@1@S@Consequently, inhibition of NF-kappaB nuclear translocation and the expression of dominant negative mutant forms of components of the NF-kappaB activation pathway, such as IkappaBalpha or p65, prompt rapid apoptosis of T. parva-transformed T cells.@@@@1@38@@oe@16-12-2010 1037741109@GENIA Treebank@formal@@1@S@Our findings offer important insights into parasite survival strategies and demonstrate that parasite-induced constitutive NF-kappaB activation is an essential step in maintaining the transformed phenotype of the infected cells.@@@@1@30@@oe@16-12-2010 1037889501@GENIA Treebank@formal@@1@S@Downregulation of Wilms' tumor gene (WT1) is not a prerequisite for erythroid or megakaryocytic differentiation of the leukemic cell line K562.@@@@1@25@@oe@16-12-2010 1037889502@GENIA Treebank@formal@@1@S@The Wilms' tumor gene (WT1) encodes a transcription factor of the zinc finger type.@@@@1@18@@oe@16-12-2010 1037889503@GENIA Treebank@formal@@1@S@A high expression of WT1 has been detected in a range of acute leukemias, and WT1 is downregulated during induced differentiation of some leukemic cell lines.@@@@1@28@@oe@16-12-2010 1037889504@GENIA Treebank@formal@@1@S@Overexpression of WT1 in some myeloid cell lines confers resistance to differentiation induction.@@@@1@14@@oe@16-12-2010 1037889505@GENIA Treebank@formal@@1@S@These observations suggest that a high WT1 expression in hematopoietic cells is incompatible with differentiation.@@@@1@16@@oe@16-12-2010 1037889506@GENIA Treebank@formal@@1@S@In this study, each of the four different isoforms of WT1 was constitutively overexpressed in the leukemic cell line K562.@@@@1@22@@oe@16-12-2010 1037889507@GENIA Treebank@formal@@1@S@K562 cells express endogenous WT1, which is downregulated as a response to induced differentiation along the erythroid and megakaryocytic pathways.@@@@1@22@@oe@16-12-2010 1037889508@GENIA Treebank@formal@@1@S@We now demonstrate that a forced exogenous expression of the four different isoforms of WT1 in K562 does not affect the differentiation response, as judged by accumulation of hemoglobin in response to hemin or the expression of megakaryocytic cell surface markers in response to 12-O-tetradecanoylphorbol-13-acetate (TPA).@@@@1@50@@oe@16-12-2010 1037889509@GENIA Treebank@formal@@1@S@We conclude that downregulation of WT1 during induced differentiation of K562 cells is not a prerequisite for erythroid or megakaryocytic differentiation of these cells.@@@@1@25@@oe@16-12-2010 1037889601@GENIA Treebank@formal@@1@S@Signal transduction pathways in normal human monocytes stimulated by cytokines and mediators: comparative study with normal human neutrophils or transformed cells and the putative roles in functionality and cell biology.@@@@1@32@@oe@16-12-2010 1037889602@GENIA Treebank@formal@@1@S@Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL) -3 induced tyrosine phosphorylation of 92-kDa protein in normal human monocytes.@@@@1@23@@oe@16-12-2010 1037889603@GENIA Treebank@formal@@1@S@We identified this 92-kDa protein as STAT5, but not as STATs1, 3, and 6 nor c-fes and vav protooncogene products, and demonstrated its translocation to the nucleus, enhancement of specific DNA binding capacity, and potentiation of trancriptional activity by GM-CSF.@@@@1@47@@oe@16-12-2010 1037889604@GENIA Treebank@formal@@1@S@N-formyl-methionyl-leucyl-phenylalanine (FMLP) and phorbol myristate acetate (PMA) induced tyrosine phosphorylation of 42- and 44-kDa proteins, which were identified as extracellular signal-regulated kinase (ERK), in human monocytes.@@@@1@35@@oe@16-12-2010 1037889605@GENIA Treebank@formal@@1@S@In marked contrast to neutrophils and MO7e cells, GM-CSF did not induce tyrosine phosphorylation and activation of ERK in monocytes.@@@@1@22@@oe@16-12-2010 1037889606@GENIA Treebank@formal@@1@S@Among upstream signaling molecules of ERK, Shc was constitutively associated with Grb2 and was not tyrosine-phosphorylated by GM-CSF and FMLP, and Sos1 and c-Raf-1 were not phosphorylated by GM-CSF, IL-3, TNF, and FMLP in monocytes, whereas all these signaling molecules were affected and/or utilized by GM-CSF in MO7e cells.@@@@1@56@@oe@16-12-2010 1037889607@GENIA Treebank@formal@@1@S@In contrast to neutrophils, p38 was constitutively phosphorylated and agonist-dependent phosphorylation and activation was not detected in human monocytes.@@@@1@21@@oe@16-12-2010 1037889608@GENIA Treebank@formal@@1@S@Superoxide release stimulated by FMLP was inhibited partially by PD98059 or SB203580, a specific inhibitor of ERK or p38 pathway, and was almost completely inhibited by the combination of both inhibitors, whereas PMA-induced superoxide release was resistant to these two inhibitors in monocytes.@@@@1@47@@oe@16-12-2010 1037889609@GENIA Treebank@formal@@1@S@PD98059 inhibited GM-CSF-dependent proliferation of MO7e cells.@@@@1@8@@oe@16-12-2010 1037889610@GENIA Treebank@formal@@1@S@Present results indicate trancriptional roles of STAT5 and functional roles of ERK and/or p38 in normal human monocytes stimulated by physiological receptor-mediated agonists GM-CSF and FMLP.@@@@1@27@@oe@16-12-2010 1037889611@GENIA Treebank@formal@@1@S@Possible roles of ERK in proliferation of transformed cells were also suggested.@@@@1@13@@oe@16-12-2010 1038091501@GENIA Treebank@formal@@1@S@Tyrphostin AG-490 inhibits cytokine-mediated JAK3/STAT5a/b signal transduction and cellular proliferation of antigen-activated human T cells.@@@@1@16@@oe@16-12-2010 1038091502@GENIA Treebank@formal@@1@S@Janus kinase 3 (JAK3) is a cytoplasmic tyrosine kinase required for T cell development and activated by cytokines that utilize the interleukin-2 (IL-2) receptor common gamma chain (gamma(c)).@@@@1@35@@oe@16-12-2010 1038091503@GENIA Treebank@formal@@1@S@Genetic inactivation of JAK3 is manifested as severe combined immunodeficiency disease (SCID) in humans and mice.@@@@1@19@@oe@16-12-2010 1038091504@GENIA Treebank@formal@@1@S@These findings have suggested that JAK3 represents a pharmacological target to control certain lymphoid-derived diseases.@@@@1@16@@oe@16-12-2010 1038091505@GENIA Treebank@formal@@1@S@Here we provide novel evidence that AG-490 potently inhibits the autokinase activity of JAK3 and tyrosine phosphorylation and DNA binding of signal transducer and activator of transcription 5a and 5b (STAT5a/b).@@@@1@34@@oe@16-12-2010 1038091506@GENIA Treebank@formal@@1@S@Similar inhibitory effects were observed with other cytokines that use gamma(c).@@@@1@12@@oe@16-12-2010 1038091507@GENIA Treebank@formal@@1@S@AG-490 also inhibited IL-2-mediated proliferative growth in human T cells with an IC50) = 25 microM that was partially recoverable.@@@@1@21@@oe@16-12-2010 1038091508@GENIA Treebank@formal@@1@S@Moreover, we demonstrate that this inhibitor prevented tetanus toxoid antigen-specific T cell proliferation and expansion but failed to block activation of Zap70 or p56Lck after anti-CD3 stimulation of human T cells.@@@@1@33@@oe@16-12-2010 1038091509@GENIA Treebank@formal@@1@S@Taken together, these findings suggest that AG-490 inhibits the JAK3-mediated Type II signaling pathway but not the T cell receptor-derived Type I pathway and possesses therapeutic potential for T cell-derived pathologies such as graft-versus-host disease, allergy, and autoimmune disorders.@@@@1@43@@oe@16-12-2010 1038150001@GENIA Treebank@formal@@1@S@Genetic evidence for an additional factor required for erythropoietin-induced signal transduction.@@@@1@12@@oe@16-12-2010 1038150002@GENIA Treebank@formal@@1@S@Erythropoietin (EPO) and its receptor (EPOR) are required for the development of mature erythrocytes.@@@@1@19@@oe@16-12-2010 1038150003@GENIA Treebank@formal@@1@S@After binding of ligand, the EPOR activates a variety of signaling pathways that ultimately control cellular proliferation, survival, and specific gene expression.@@@@1@26@@oe@16-12-2010 1038150004@GENIA Treebank@formal@@1@S@Although erythroid progenitors appear to be the principal EPO-responsive cell type in vivo due to the restricted expression of the EPOR, many growth factor-dependent cell lines expressing the EPOR can respond to EPO by activating many or all of these pathways.@@@@1@43@@oe@16-12-2010 1038150005@GENIA Treebank@formal@@1@S@In the present study, we have identified a cellular context (the interleukin-2 [IL-2]-dependent HT-2 line) in which the EPO stimulation of the EPOR fails to support cellular proliferation, STAT-5 induction, or MAPK activation, despite efficient phosphorylation of the EPOR and JAK2 and inhibition of apoptosis after withdrawal of IL-2.@@@@1@59@@oe@16-12-2010 1038150006@GENIA Treebank@formal@@1@S@Interestingly, when we fused HT-2 cells expressing the EPOR with Ba/F3 cells in a complementation assay, the resulting hybridomas proliferated and potently activated STAT-5 and MAPK in response to EPO.@@@@1@33@@oe@16-12-2010 1038150007@GENIA Treebank@formal@@1@S@These data indicate that an unidentified cellular factor is needed to mediate signaling by the EPOR.@@@@1@17@@oe@16-12-2010 1038150008@GENIA Treebank@formal@@1@S@Moreover, Ba/F3 cells apparently express this factor(s) and somatic fusions can, therefore, confer EPO-responsiveness to HT-2 cells that lack this factor.@@@@1@28@@oe@16-12-2010 1038150101@GENIA Treebank@formal@@1@S@GATA-1 and erythropoietin cooperate to promote erythroid cell survival by regulating bcl-xL expression.@@@@1@14@@oe@16-12-2010 1038150102@GENIA Treebank@formal@@1@S@The transcription factor GATA-1 is essential for normal erythropoiesis.@@@@1@10@@oe@16-12-2010 1038150103@GENIA Treebank@formal@@1@S@By examining in vitro-differentiated embryonic stem cells, we showed previously that in the absence of GATA-1, committed erythroid precursors fail to complete maturation and instead undergo apoptosis.@@@@1@30@@oe@16-12-2010 1038150104@GENIA Treebank@formal@@1@S@The mechanisms by which GATA-1 controls cell survival are unknown.@@@@1@11@@oe@16-12-2010 1038150105@GENIA Treebank@formal@@1@S@Here we report that in erythroid cells, GATA-1 strongly induces the expression of the anti-apoptotic protein bcl-xL, but not the related proteins bcl-2 and mcl-1.@@@@1@28@@oe@16-12-2010 1038150106@GENIA Treebank@formal@@1@S@Consistent with a role for bcl-xL in mediating GATA-1-induced erythroid cell survival, in vitro-differentiated bcl-xL-/- embryonic stem cells fail to generate viable mature definitive erythroid cells, a phenotype resembling that of GATA-1 gene disruption.@@@@1@37@@oe@16-12-2010 1038150107@GENIA Treebank@formal@@1@S@In addition, we show that erythropoietin, which is also required for erythroid cell survival, cooperates with GATA-1 to stimulate bcl-xL gene expression and to maintain erythroid cell viability during terminal maturation.@@@@1@35@@oe@16-12-2010 1038150108@GENIA Treebank@formal@@1@S@Together, our data show that bcl-xL is essential for normal erythroid development and suggest a regulatory hierarchy in which bcl-xL is a critical downstream effector of GATA-1 and erythropoietin-mediated signals.@@@@1@32@@oe@16-12-2010 1038165501@GENIA Treebank@formal@@1@S@NF-kappaB functions as both a proapoptotic and antiapoptotic regulatory factor within a single cell type.@@@@1@16@@oe@16-12-2010 1038165502@GENIA Treebank@formal@@1@S@Recently NF-kappaB has been shown to have both proapoptotic and antiapoptotic functions.@@@@1@13@@oe@16-12-2010 1038165503@GENIA Treebank@formal@@1@S@In T cell hybridomas, both T cell activators and glucocorticoids induce apoptosis.@@@@1@14@@oe@16-12-2010 1038165504@GENIA Treebank@formal@@1@S@Here we show that blockade of NF-kappaB activity, using a dominant negative IkappaBalpha, has opposite effects on these two apoptotic signals.@@@@1@24@@oe@16-12-2010 1038165505@GENIA Treebank@formal@@1@S@Treatment with PMA plus ionomycin (P/I) results in the upregulation of Fas Ligand (FasL) and induction of apoptosis.@@@@1@23@@oe@16-12-2010 1038165506@GENIA Treebank@formal@@1@S@Inhibition of NF-kappaB activity inhibits the P/I mediated induction of FasL mRNA and decreases the level of apoptosis in these cultures, thus establishing NF-kappaB as a proapoptotic factor in this context.@@@@1@33@@oe@16-12-2010 1038165507@GENIA Treebank@formal@@1@S@Conversely, inhibition of NF-kappaB confers a tenfold increase in glucocorticoid mediated apoptosis, establishing that NF-kappaB also functions as an antiapoptotic factor.@@@@1@24@@oe@16-12-2010 1038165508@GENIA Treebank@formal@@1@S@We conclude that NF-kappaB is a context-dependent apoptosis regulator.@@@@1@10@@oe@16-12-2010 1038165509@GENIA Treebank@formal@@1@S@Our data suggests that NF-kappaB may function as an antiapoptotic factor in thymocytes while functioning as a proapoptotic factor in mature peripheral T cells.@@@@1@25@@oe@16-12-2010 1038339701@GENIA Treebank@formal@@1@S@3-deazaadenosine, a S-adenosylhomocysteine hydrolase inhibitor, has dual effects on NF-kappaB regulation.@@@@1@14@@oe@16-12-2010 1038339702@GENIA Treebank@formal@@1@S@Inhibition of NF-kappaB transcriptional activity and promotion of IkappaBalpha degradation.@@@@1@11@@oe@16-12-2010 1038339703@GENIA Treebank@formal@@1@S@Previously we reported that 3-deazaadenosine (DZA), a potent inhibitor and substrate for S-adenosylhomocysteine hydrolase inhibits bacterial lipopolysaccharide-induced transcription of tumor necrosis factor-alpha and interleukin-1beta in mouse macrophage RAW 264.7 cells.@@@@1@34@@oe@16-12-2010 1038339704@GENIA Treebank@formal@@1@S@In this study, we demonstrate the effects of DZA on nuclear factor-kappaB (NF-kappaB) regulation.@@@@1@18@@oe@16-12-2010 1038339705@GENIA Treebank@formal@@1@S@DZA inhibits the transcriptional activity of NF-kappaB through the hindrance of p65 (Rel-A) phosphorylation without reduction of its nuclear translocation and DNA binding activity.@@@@1@27@@oe@16-12-2010 1038339706@GENIA Treebank@formal@@1@S@The inhibitory effect of DZA on NF-kappaB transcriptional activity is potentiated by the addition of homocysteine.@@@@1@17@@oe@16-12-2010 1038339707@GENIA Treebank@formal@@1@S@Taken together, DZA promotes the proteolytic degradation of IkappaBalpha, but not IkappaBbeta, resulting in an increase of DNA binding activity of NF-kappaB in the nucleus in the absence of its transcriptional activity in RAW 264.7 cells.@@@@1@40@@oe@16-12-2010 1038339708@GENIA Treebank@formal@@1@S@The reduction of IkappaBalpha by DZA is neither involved in IkappaB kinase complex activation nor modulated by the addition of homocysteine.@@@@1@22@@oe@16-12-2010 1038339709@GENIA Treebank@formal@@1@S@This study strongly suggests that DZA may be a potent drug for the treatment of diseases in which NF-kappaB plays a central pathogenic role, as well as a useful tool for studying the regulation and physiological functions of NF-kappaB.@@@@1@41@@oe@16-12-2010 1038394001@GENIA Treebank@formal@@1@S@STAT1 activation during monocyte to macrophage maturation: role of adhesion molecules.@@@@1@13@@oe@16-12-2010 1038394002@GENIA Treebank@formal@@1@S@Human monocytes isolated from peripheral blood of healthy donors show a time-dependent differentiation into macrophages upon in vitro cultivation, closely mimicking their in vivo migration and maturation into extravascular tissues.@@@@1@32@@oe@16-12-2010 1038394003@GENIA Treebank@formal@@1@S@The mediator(s) of this maturation process has not been yet defined.@@@@1@15@@oe@16-12-2010 1038394004@GENIA Treebank@formal@@1@S@We investigated the involvement of signal transducers and activators of transcription (STAT) factors in this phenomenon and reported the specific, time-dependent, activation of STAT1 protein starting at day 0/1 of cultivation and maximally expressed at day 5.@@@@1@42@@oe@16-12-2010 1038394005@GENIA Treebank@formal@@1@S@STAT1 activity was evident on the STAT binding sequences (SBE) present in the promoters of genes which are up-regulated during monocyte to macrophage maturation such as FcgammaRI and ICAM-1, and in the promoter of the transcription factor IFN regulatory factor-1.@@@@1@44@@oe@16-12-2010 1038394006@GENIA Treebank@formal@@1@S@Moreover, the effect of cell adhesion to fibronectin or laminin was studied to investigate mechanisms involved in STAT1 activation.@@@@1@21@@oe@16-12-2010 1038394007@GENIA Treebank@formal@@1@S@Compared with monocytes adherent on plastic surfaces, freshly isolated cells allowed to adhere either to fibronectin- or laminin-coated flasks exhibited an increased STAT1 binding activity both in control and in IFN-gamma-treated cells.@@@@1@34@@oe@16-12-2010 1038394008@GENIA Treebank@formal@@1@S@The molecular events leading to enhanced STAT1 activation and cytokine responsiveness concerned both Y701 and S727 STAT1 phosphorylation.@@@@1@19@@oe@16-12-2010 1038394009@GENIA Treebank@formal@@1@S@Exogenous addition of transforming growth factor-beta, which exerts an inhibitory effect on some monocytic differentiation markers, inhibited macrophage maturation, integrin expression and STAT1 binding activity.@@@@1@29@@oe@16-12-2010 1038394010@GENIA Treebank@formal@@1@S@Taken together these results indicate that STAT1 plays a pivotal role in the differentiation/maturation process of monocytes as an early transcription factor initially activated by adherence and then able to modulate the expression of functional genes, such as ICAM-1 and FcgammaRI.@@@@1@43@@oe@16-12-2010 1038409401@GENIA Treebank@formal@@1@S@Cutting edge: expression of the NF of activated T cells in eosinophils: regulation by IL-4 and IL-5.@@@@1@20@@oe@16-12-2010 1038409402@GENIA Treebank@formal@@1@S@We report that NF-AT1 and NF-AT4 are expressed cytoplasmically in resting eosinophils, whereas NF-AT2 and NF-AT3 have not been seen.@@@@1@22@@oe@16-12-2010 1038409403@GENIA Treebank@formal@@1@S@Likewise, NF-AT1 mRNA and NF-AT4 mRNA have been detected in resting eosinophils, and their levels can be significantly up-regulated by the Th2-associated cytokines IL-4 and IL-5.@@@@1@29@@oe@16-12-2010 1038409404@GENIA Treebank@formal@@1@S@There is no detectable NF-AT protein expression in the nuclei of resting eosinophils.@@@@1@14@@oe@16-12-2010 1038409405@GENIA Treebank@formal@@1@S@However NF-ATs appear in the nuclei of IL-4-, IL-5-, or ionomycin-stimulated eosinophils.@@@@1@15@@oe@16-12-2010 1038409406@GENIA Treebank@formal@@1@S@Only NF-AT1 and NF-AT4, but not NF-AT2 and NF-AT3, have translocated into the nuclei in IL-4- or IL-5-stimulated eosinophils.@@@@1@22@@oe@16-12-2010 1038409407@GENIA Treebank@formal@@1@S@These findings delineate a novel pathway in the cytokine network in which Th2 lymphocytes "control" eosinophils via the release of IL-4 and IL-5, and activation of NF-AT in eosinophils.@@@@1@33@@oe@16-12-2010 1038409408@GENIA Treebank@formal@@1@S@The findings also suggest that a later feedback "talking" may exist between eosinophils and Th2 lymphocytes.@@@@1@19@@oe@16-12-2010 1038415301@GENIA Treebank@formal@@1@S@Altered memory T cell differentiation in patients with early rheumatoid arthritis.@@@@1@12@@oe@16-12-2010 1038415302@GENIA Treebank@formal@@1@S@The chronic immune response in rheumatoid arthritis (RA) might be driven by activated Th1 cells without sufficient Th2 cell differentiation to down-modulate inflammation.@@@@1@26@@oe@16-12-2010 1038415303@GENIA Treebank@formal@@1@S@To test whether disordered memory T cell differentiation contributes to the typical Th1-dominated chronic inflammation in RA we investigated differentiation of resting CD4+ memory T cells in patients with early (6 wk to 12 mo) untreated RA and in age- and sex-matched healthy controls in vitro.@@@@1@49@@oe@16-12-2010 1038415304@GENIA Treebank@formal@@1@S@No difference in cytokine secretion profiles of freshly isolated memory T cells was detected between patients and controls.@@@@1@19@@oe@16-12-2010 1038415305@GENIA Treebank@formal@@1@S@A cell culture system was then employed that permitted the differentiation of Th effectors from resting memory T cells by short term priming.@@@@1@24@@oe@16-12-2010 1038415306@GENIA Treebank@formal@@1@S@Marked differences were found in response to priming.@@@@1@9@@oe@16-12-2010 1038415307@GENIA Treebank@formal@@1@S@Th2 cells could be induced in all healthy controls by priming with anti-CD28 in the absence of TCR ligation.@@@@1@20@@oe@16-12-2010 1038415308@GENIA Treebank@formal@@1@S@By contrast, priming under those conditions resulted in Th2 differentiation in only 9 of 24 RA patients.@@@@1@19@@oe@16-12-2010 1038415309@GENIA Treebank@formal@@1@S@Exogenous IL-4 could overcome the apparent Th2 differentiation defect in seven patients but was without effect in the remaining eight patients.@@@@1@22@@oe@16-12-2010 1038415310@GENIA Treebank@formal@@1@S@In all patients a marked decrease in IL-2-producing cells and a significant increase in well-differentiated Th1 cells that produced IFN-gamma but not IL-2 were evident after priming with anti-CD3 and anti-CD28.@@@@1@32@@oe@16-12-2010 1038415311@GENIA Treebank@formal@@1@S@The data suggest that CD4+ memory T cells from patients with early untreated RA manifest an intrinsic abnormality in their ability to differentiate into specific cytokine-producing effector cells that might contribute to the characteristic Th1-dominated chronic (auto)immune inflammation in RA.@@@@1@44@@oe@16-12-2010 1038565001@GENIA Treebank@formal@@1@S@Functional B-cell response in intrahepatic lymphoid follicles in chronic hepatitis C.@@@@1@12@@oe@16-12-2010 1038565002@GENIA Treebank@formal@@1@S@Intrahepatic lymphoid follicle (ILF) formation is one of the most characteristic and commonly observed histological features in patients with chronic hepatitis C.@@@@1@25@@oe@16-12-2010 1038565003@GENIA Treebank@formal@@1@S@However, little is known regarding whether follicles in the liver belong to functional lymphoid tissues, where B cells are activated, differentiated, and proliferated, or if the lymphocytes are merely infiltrated after recruitment from the secondary lymphoid organs.@@@@1@43@@oe@16-12-2010 1038565004@GENIA Treebank@formal@@1@S@To ascertain this possibility, we examined the expression of markers for B-cell activation, differentiation, and proliferation in ILFs in patients with chronic hepatitis C using surgically resected specimens, and compared them with specimens of perihepatic lymph nodes by an immunohistochemical technique.@@@@1@46@@oe@16-12-2010 1038565005@GENIA Treebank@formal@@1@S@Germinal center (GC) formation in the ILFs was frequently found in HCV-positive cases.@@@@1@16@@oe@16-12-2010 1038565006@GENIA Treebank@formal@@1@S@The distribution of immunoglobulin M (IgM)-, IgD-, and IgG-positive cells and the expression patterns of Ki-67, CD23, or bcl-2 and bcl-6 gene products in the follicles with GC formation in the liver of patients with chronic hepatitis C were similar to those of lymph nodes, indicating that B cells are activated, proliferated, and differentiated in the ILFs with GC formation in patients with chronic hepatitis C.@@@@1@77@@oe@16-12-2010 1038565007@GENIA Treebank@formal@@1@S@Oligoclonal expansion of B cells in the livers with ILFs was confirmed by an analysis of immunoglobulin heavy chain (IgH) gene rearrangement determined by polymerase chain reaction (PCR).@@@@1@33@@oe@16-12-2010 1038565008@GENIA Treebank@formal@@1@S@These data strongly suggest that ILFs with GC formation, which are frequently found in patients with chronic hepatitis C, may functionally be the same as those found in lymph nodes with respect to B-cell expansion and maturation.@@@@1@40@@oe@16-12-2010 1039520101@GENIA Treebank@formal@@1@S@Ovarian and breast cytotoxic T lymphocytes can recognize peptides from the amino enhancer of split protein of the Notch complex.@@@@1@21@@oe@16-12-2010 1039520102@GENIA Treebank@formal@@1@S@In this study we investigated recognition by ovarian tumor associated lymphocyte (OVTAL), and breast tumor associated lymphocytes (BRTAL), of peptides corresponding to the sequence 125-135 of the Aminoenhancer of split (AES) protein.@@@@1@41@@oe@16-12-2010 1039520103@GENIA Treebank@formal@@1@S@Three of these peptides designated as G75:AES1/2 (128-135), G60: AES1/2 (127-137) and G61: AES1/2 (125-133) correspond to the wildtype AES sequence, while the fourth G76:GPLTPLPV, AES1/2 (128-135) corresponds to a variant sequence of the peptide G75 with the N-terminal Leu substituted to glycine.@@@@1@53@@oe@16-12-2010 1039520104@GENIA Treebank@formal@@1@S@These sequences were chosen for study because mass-spectrometric analysis (MS) of a CTL active HPLC peptide fraction eluted from immunoaffinity precipitated HLA-A2 molecule, revealed: (a) the presence of an ion with a mass-to-charge ratio (m/z) of 793 which was more abundant than other ions of similar masses; (b) the tentatively reconstituted sequence of the ion 793 matched the sequence of peptide G76.@@@@1@74@@oe@16-12-2010 1039520105@GENIA Treebank@formal@@1@S@We found that AES peptides G75 (128-135) and G76 (128-135) (L128G) reconstituted CTL recognition at concentrations ranging between 200-500 nM.@@@@1@27@@oe@16-12-2010 1039520106@GENIA Treebank@formal@@1@S@These concentrations are lower than concentrations reported to activate effector function of CTL recognizing other epithelial tumor Ag.@@@@1@19@@oe@16-12-2010 1039520107@GENIA Treebank@formal@@1@S@Furthermore, analysis with cloned CD8+ T cells indicated that G75 and G76 were not cross-reactive specificities, suggesting a key role for the N-terminal residues of the variant peptide in dictating specificities.@@@@1@34@@oe@16-12-2010 1039520108@GENIA Treebank@formal@@1@S@Since the AES proteins are part of a set of transcriptional repressors encoded by the Enhancer of split [E(spl)] genes, and since these repressors are activated to suppress cell differentiation in response to Notch receptors signalling, the AES peptides may represent a novel class of self-antigens that deserve further consideration as tumor Ag in epithelial cancers.@@@@1@61@@oe@16-12-2010 1039564501@GENIA Treebank@formal@@1@S@Inhibition of NF-kappa B activity in human T lymphocytes induces caspase-dependent apoptosis without detectable activation of caspase-1 and -3.@@@@1@20@@oe@16-12-2010 1039564502@GENIA Treebank@formal@@1@S@NF-kappa B is involved in the transcriptional control of various genes that act as extrinsic and intrinsic survival factors for T cells.@@@@1@23@@oe@16-12-2010 1039564503@GENIA Treebank@formal@@1@S@Our findings show that suppression of NF-kappa B activity with cell-permeable SN50 peptide, which masks the nuclear localization sequence of NF-kappa B1 dimers and prevents their nuclear localization, induces apoptosis in resting normal human PBL.@@@@1@38@@oe@16-12-2010 1039564504@GENIA Treebank@formal@@1@S@Inhibition of NF-kappa B resulted in the externalization of phosphatidylserine, induction of DNA breaks, and morphological changes consistent with apoptosis.@@@@1@23@@oe@16-12-2010 1039564505@GENIA Treebank@formal@@1@S@DNA fragmentation was efficiently blocked by the caspase inhibitor Z-VAD-fmk and partially blocked by Ac-DEVD-fmk, suggesting that SN50-mediated apoptosis is caspase-dependent.@@@@1@23@@oe@16-12-2010 1039564506@GENIA Treebank@formal@@1@S@Interestingly, apoptosis induced by NF-kappa B suppression, in contrast to that induced by TPEN (N,N,N',N'-tetrakis [2-pyridylmethyl]ethylenediamine) or soluble Fas ligand (CD95), was observed in the absence of active death effector proteases caspase-1-like (IL-1 converting enzyme), caspase-3-like (CPP32/Yama/apopain), and caspase-6-like and without cleavage of caspase-3 substrates poly(ADP-ribose) polymerase and DNA fragmentation factor-45.@@@@1@65@@oe@16-12-2010 1039564507@GENIA Treebank@formal@@1@S@These findings suggest either low level of activation is required or that different caspases are involved.@@@@1@17@@oe@16-12-2010 1039564508@GENIA Treebank@formal@@1@S@Preactivation of T cells resulting in NF-kappa B nuclear translocation protected cells from SN50-induced apoptosis.@@@@1@16@@oe@16-12-2010 1039564509@GENIA Treebank@formal@@1@S@Our findings demonstrate an essential role of NF-kappa B in survival of naive PBL.@@@@1@15@@oe@16-12-2010 1039565201@GENIA Treebank@formal@@1@S@Signaling events induced by lipopolysaccharide-activated toll-like receptor 2.@@@@1@9@@oe@16-12-2010 1039565202@GENIA Treebank@formal@@1@S@Human Toll-like receptor 2 (TLR2) is a signaling receptor that responds to LPS and activates NF-kappaB.@@@@1@19@@oe@16-12-2010 1039565203@GENIA Treebank@formal@@1@S@Here, we investigate further the events triggered by TLR2 in response to LPS.@@@@1@15@@oe@16-12-2010 1039565204@GENIA Treebank@formal@@1@S@We show that TLR2 associates with the high-affinity LPS binding protein membrane CD14 to serve as an LPS receptor complex, and that LPS treatment enhances the oligomerization of TLR2.@@@@1@31@@oe@16-12-2010 1039565205@GENIA Treebank@formal@@1@S@Concomitant with receptor oligomerization, the IL-1R-associated kinase (IRAK) is recruited to the TLR2 complex.@@@@1@18@@oe@16-12-2010 1039565206@GENIA Treebank@formal@@1@S@Intracellular deletion variants of TLR2 lacking C-terminal 13 or 141 aa fail to recruit IRAK, which is consistent with the inability of these mutants to transmit LPS cellular signaling.@@@@1@31@@oe@16-12-2010 1039565207@GENIA Treebank@formal@@1@S@Moreover, both deletion mutants could still form complexes with wild-type TLR2 and act in a dominant-negative (DN) fashion to block TLR2-mediated signal transduction.@@@@1@27@@oe@16-12-2010 1039565208@GENIA Treebank@formal@@1@S@DN constructs of myeloid differentiation protein, IRAK, TNF receptor-associated factor 6, and NF-kappaB-inducing kinase, when coexpressed with TLR2, abrogate TLR2-mediated NF-kappaB activation.@@@@1@28@@oe@16-12-2010 1039565209@GENIA Treebank@formal@@1@S@These results reveal a conserved signaling pathway for TLR2 and IL-1Rs and suggest a molecular mechanism for the inhibition of TLR2 by DN variants.@@@@1@25@@oe@16-12-2010 1039567101@GENIA Treebank@formal@@1@S@Activation of the Janus kinase 3-STAT5a pathway after CD40 triggering of human monocytes but not of resting B cells.@@@@1@20@@oe@16-12-2010 1039567102@GENIA Treebank@formal@@1@S@CD40/CD40 ligand interactions play a key role in the immune responses of B lymphocytes, monocytes, and dendritic cells.@@@@1@21@@oe@16-12-2010 1039567103@GENIA Treebank@formal@@1@S@The signal transduction events triggered by cross-linking of the CD40 receptor have been widely studied in B cell lines, but little is known about signaling following CD40 stimulation of monocytes and resting tonsillar B cells.@@@@1@37@@oe@16-12-2010 1039567104@GENIA Treebank@formal@@1@S@Therefore, we studied the CD40 pathway in highly purified human monocytes and resting B cells.@@@@1@17@@oe@16-12-2010 1039567105@GENIA Treebank@formal@@1@S@After CD40 triggering, a similar activation of the NF-kappaB (but not of the AP-1) transcription factor complex occurred in both cell preparations.@@@@1@26@@oe@16-12-2010 1039567106@GENIA Treebank@formal@@1@S@However, the components of the NF-kappaB complexes were different in monocytes and B cells, because p50 is part of the NF-kappaB complex induced by CD40 triggering in both monocytes and B cells, whereas p65 was only induced in B cells.@@@@1@44@@oe@16-12-2010 1039567107@GENIA Treebank@formal@@1@S@In contrast, although the Janus kinase 3 tyrosine kinase was associated with CD40 molecules in both monocytes and resting B cells, Janus kinase 3 phosphorylation induction was observed only in CD40-activated monocytes, with subsequent induction of STAT5a DNA binding activity in the nucleus.@@@@1@47@@oe@16-12-2010 1039567108@GENIA Treebank@formal@@1@S@These results suggest that the activation signals in human B cells and monocytes differ following CD40 stimulation.@@@@1@18@@oe@16-12-2010 1039567109@GENIA Treebank@formal@@1@S@This observation is consistent with the detection of normal CD40-induced monocyte activation in patients with CD40 ligand+ hyper IgM syndrome in whom a defect in CD40-induced B cell activation has been reported.@@@@1@33@@oe@16-12-2010 1039629001@GENIA Treebank@formal@@1@S@Clonality analysis using X-chromosome inactivation at the human androgen receptor gene (Humara).@@@@1@15@@oe@16-12-2010 1039629002@GENIA Treebank@formal@@1@S@Evaluation of large cohorts of patients with chronic myeloproliferative diseases, secondary neutrophilia, and reactive thrombocytosis.@@@@1@18@@oe@16-12-2010 1039629003@GENIA Treebank@formal@@1@S@Chronic myeloproliferative diseases (MPDs) are not associated with consistent cytogenetic or molecular abnormalities.@@@@1@16@@oe@16-12-2010 1039629004@GENIA Treebank@formal@@1@S@Demonstration of clonal cell growth by analysis of X-chromosome inactivation (XCI) patterns in females provides a promising tool for diagnosis.@@@@1@23@@oe@16-12-2010 1039629005@GENIA Treebank@formal@@1@S@However, this technique can be complicated by excessive lyonization of normal cells mimicking clonal cell growth: We analyzed XCI patterns at the human androgen receptor (HUMARA) locus in 146 healthy females, 65 women with secondary neutrophilia, 31 women with reactive thrombocytosis, and 86 women with chronic MPDs.@@@@1@55@@oe@16-12-2010 1039629006@GENIA Treebank@formal@@1@S@A skewed XCI pattern with greater than 75% amplification of 1 allele (allele ratio > 3:1) was found in 22 (9.1%) of 242 control subjects.@@@@1@34@@oe@16-12-2010 1039629007@GENIA Treebank@formal@@1@S@The incidence of skewing was statistically significantly lower in women younger than 30 years (2/73) compared with women older than 60 years (10/53).@@@@1@28@@oe@16-12-2010 1039629008@GENIA Treebank@formal@@1@S@Of 86 patients with a chronic MPD, 71 (82%) exhibited an allele ratio greater than 3:1, whereas only 10 (12%) of 86 age-matched control subjects showed a skewed XCI pattern.@@@@1@41@@oe@16-12-2010 1039629009@GENIA Treebank@formal@@1@S@Although statistical evaluation of the data showed a significant difference between patients with a chronic MPD and control subjects, proof of clonality in individual, especially elderly, patients is difficult.@@@@1@33@@oe@16-12-2010 1039772201@GENIA Treebank@formal@@1@S@The glucocorticoid receptor cooperates with the erythropoietin receptor and c-Kit to enhance and sustain proliferation of erythroid progenitors in vitro.@@@@1@21@@oe@16-12-2010 1039772202@GENIA Treebank@formal@@1@S@Although erythropoietin (Epo) is essential for the production of mature red blood cells, the cooperation with other factors is required for a proper balance between progenitor proliferation and differentiation.@@@@1@33@@oe@16-12-2010 1039772203@GENIA Treebank@formal@@1@S@In avian erythroid progenitors, steroid hormones cooperate with tyrosine kinase receptors to induce renewal of erythroid progenitors.@@@@1@19@@oe@16-12-2010 1039772204@GENIA Treebank@formal@@1@S@We examined the role of corticosteroids in the in vitro expansion of primary human erythroid cells in liquid cultures and colony assays.@@@@1@23@@oe@16-12-2010 1039772205@GENIA Treebank@formal@@1@S@Dexamethasone (Dex), a synthetic glucocorticoid hormone, cooperated with Epo and stem cell factor to induce erythroid progenitors to undergo 15 to 22 cell divisions, corresponding to a 10(5)- to 10(6)-fold amplification of erythroid cells.@@@@1@40@@oe@16-12-2010 1039772206@GENIA Treebank@formal@@1@S@Dex acted directly on erythroid progenitors and maintained the colony-forming capacity of the progenitor cells expanded in liquid cultures.@@@@1@20@@oe@16-12-2010 1039772207@GENIA Treebank@formal@@1@S@The hormone delayed terminal differentiation into erythrocytes, which was assayed by morphology, hemoglobin accumulation, and the expression of genes characteristic for immature cells.@@@@1@27@@oe@16-12-2010 1039772208@GENIA Treebank@formal@@1@S@Sustained proliferation of erythroid progenitors could be induced equally well from purified erythroid burst-forming units (BFU-E), from CD34(+) blast cells, and from bone marrow depleted from CD34(+) cells.@@@@1@33@@oe@16-12-2010 1040075501@GENIA Treebank@formal@@1@S@Escape of human cytomegalovirus from HLA-DR-restricted CD4(+) T-cell response is mediated by repression of gamma interferon-induced class II transactivator expression.@@@@1@21@@oe@16-12-2010 1040075502@GENIA Treebank@formal@@1@S@Human cytomegalovirus (HCMV), a betaherpesvirus, is a pathogen which escapes immune recognition through various mechanisms.@@@@1@20@@oe@16-12-2010 1040075503@GENIA Treebank@formal@@1@S@In this paper, we show that HCMV down regulates gamma interferon (IFN-gamma)-induced HLA-DR expression in U373 MG astrocytoma cells due to a defect downstream of STAT1 phosphorylation and nuclear translocation.@@@@1@35@@oe@16-12-2010 1040075504@GENIA Treebank@formal@@1@S@Repression of class II transactivator (CIITA) mRNA expression is detected within the first hours of IFN-gamma-HCMV coincubation and results in the absence of HLA-DR synthesis.@@@@1@28@@oe@16-12-2010 1040075505@GENIA Treebank@formal@@1@S@This defect leads to the absence of presentation of the major immediate-early protein IE1 to specific CD4(+) T-cell clones when U373 MG cells, used as antigen-presenting cells, are treated with IFN-gamma plus HCMV.@@@@1@36@@oe@16-12-2010 1040075506@GENIA Treebank@formal@@1@S@However, presentation of endogenously synthesized IE1 can be restored when U373 MG cells are transfected with CIITA prior to infection with HCMV.@@@@1@24@@oe@16-12-2010 1040075507@GENIA Treebank@formal@@1@S@Altogether, the data indicate that the defect induced by HCMV resides in the activation of the IFN-gamma-responsive promoter of CIITA.@@@@1@22@@oe@16-12-2010 1040075508@GENIA Treebank@formal@@1@S@This is the first demonstration of a viral inhibition of CIITA expression.@@@@1@13@@oe@16-12-2010 1040217301@GENIA Treebank@formal@@1@S@Suppression of NF-kappaB activation in normal T cells by supernatant fluid from human renal cell carcinomas.@@@@1@17@@oe@16-12-2010 1040217302@GENIA Treebank@formal@@1@S@T lymphocytes from patients with renal cell carcinoma (RCC) show reduced immune function and impaired activation of the transcription factor, NF-kappaB.@@@@1@25@@oe@16-12-2010 1040217303@GENIA Treebank@formal@@1@S@We determined the mechanism of NF-kappaB suppression in T cells of RCC patient and determined whether supernatant fluid from RCC explants (RCC-S) induced the same phenotype of NF-kappaB suppression in normal T cells that is observed in patient T cells.@@@@1@43@@oe@16-12-2010 1040217304@GENIA Treebank@formal@@1@S@The pattern of kappaB-binding activity in T cells of RCC patient was altered as compared to that seen in T cells obtained from normal volunteers.@@@@1@26@@oe@16-12-2010 1040217305@GENIA Treebank@formal@@1@S@In some patients, no activation of RelA/NFkappaB1-binding activity was detectable, while in others kappaB-binding activity was modestly induced but the duration was reduced.@@@@1@26@@oe@16-12-2010 1040217306@GENIA Treebank@formal@@1@S@IkappaBalpha was degraded normally following stimulation in both normal controls and T cells from RCC patients.@@@@1@17@@oe@16-12-2010 1040217307@GENIA Treebank@formal@@1@S@RCC-S did not alter the cytoplasmic levels of RelA and NF-kappaB1 but did suppress their nuclear localization and inhibited the activation of RelA/NF-kappaB1 binding complexes.@@@@1@26@@oe@16-12-2010 1040217308@GENIA Treebank@formal@@1@S@These results show that RCC-S can induce in normal T cells the same phenotype of impaired NF-kappaB activation that is detected in T cells of RCC patient.@@@@1@28@@oe@16-12-2010 1040217309@GENIA Treebank@formal@@1@S@It also appears that NF-kappaB suppression by RCC-S may contribute to the immunosuppression of host immunity.@@@@1@17@@oe@16-12-2010 1040327001@GENIA Treebank@formal@@1@S@Monoclonal anti-endothelial cell antibodies from a patient with Takayasu arteritis activate endothelial cells from large vessels.@@@@1@17@@oe@16-12-2010 1040327002@GENIA Treebank@formal@@1@S@OBJECTIVE: To create monoclonal anti-endothelial cell antibodies (mAECA) from a patient with Takayasu arteritis to evaluate their ability to activate human umbilical vein endothelial cells (HUVEC), and to characterize the mechanism of EC activation.@@@@1@41@@oe@16-12-2010 1040327003@GENIA Treebank@formal@@1@S@METHODS: A panel of mAECA was generated from peripheral blood lymphocytes of a patient with Takayasu arteritis, using Epstein-Barr virus transformation.@@@@1@24@@oe@16-12-2010 1040327004@GENIA Treebank@formal@@1@S@Activity against macrovascular EC (HUVEC) and microvascular EC (human bone marrow EC immortalized by SV40) antigens was detected by enzyme-linked immunosorbent assay.@@@@1@27@@oe@16-12-2010 1040327005@GENIA Treebank@formal@@1@S@Inhibition studies were used to select the monoclonal antibodies (mAECA) which share the same EC epitope binding specificity as the total IgG-AECA from the Takayasu arteritis patient.@@@@1@30@@oe@16-12-2010 1040327006@GENIA Treebank@formal@@1@S@The binding of the mAECA to human aortic EC was studied by immunohistochemistry.@@@@1@14@@oe@16-12-2010 1040327007@GENIA Treebank@formal@@1@S@The secretion levels of interleukin-6 (IL-6) and von Willebrand factor (vWF) were determined, to serve as markers for EC activation.@@@@1@26@@oe@16-12-2010 1040327008@GENIA Treebank@formal@@1@S@The activated EC were examined for the adherence of a monocytic cell line (U937), as well as for expression of vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and E-selectin.@@@@1@37@@oe@16-12-2010 1040327009@GENIA Treebank@formal@@1@S@In addition, nuclear extracts of the mAECA-treated EC were analyzed for the induction of translocation of nuclear factor kappaB (NF-kappaB), using a specific NF-kappaB oligoprobe in an electrophoretic mobility shift assay.@@@@1@36@@oe@16-12-2010 1040327010@GENIA Treebank@formal@@1@S@RESULTS: Six mAECA were selected, the mixture of which produced 100% inhibition of binding of the original IgG (from the patient with Takayasu arteritis) to HUVEC.@@@@1@32@@oe@16-12-2010 1040327011@GENIA Treebank@formal@@1@S@All mAECA possessed high activity against macrovascular EC, but none had significant antimicrovascular EC activity.@@@@1@17@@oe@16-12-2010 1040327012@GENIA Treebank@formal@@1@S@The mAECA, but not normal human IgG, had anti-human aortic EC activity.@@@@1@15@@oe@16-12-2010 1040327013@GENIA Treebank@formal@@1@S@Four of the 6 mAECA activated EC, manifested by increased IL-6 and vWF secretion.@@@@1@16@@oe@16-12-2010 1040327014@GENIA Treebank@formal@@1@S@The 4 mAECA induced EC expression of adhesion molecules and increased adhesion of U937 monocytic cells to EC.@@@@1@19@@oe@16-12-2010 1040327015@GENIA Treebank@formal@@1@S@In addition, these mAECA stimulated the nuclear translocation of the NF-kappaB transcription factor.@@@@1@15@@oe@16-12-2010 1040327016@GENIA Treebank@formal@@1@S@CONCLUSION: Our findings suggest that AECA may directly stimulate EC in Takayasu arteritis through elevation of adhesion molecule expression associated with NF-kappaB activation and adhesion of monocytes, and may therefore play a pathogenic role in the development of the vasculopathy in Takayasu arteritis.@@@@1@46@@oe@16-12-2010 1040377001@GENIA Treebank@formal@@1@S@ICSAT overexpression is not sufficient to cause adult T-cell leukemia or multiple myeloma.@@@@1@14@@oe@16-12-2010 1040377002@GENIA Treebank@formal@@1@S@ICSAT (Interferon Consensus Sequence binding protein for Activated T cells) is a lymphocyte-specific member of the interferon regulatory factor (IRF) family of transcription factors, originally identified through Southwestern screening of the ATL(Adult T-cell leukemia)-16T expression library.@@@@1@46@@oe@16-12-2010 1040377003@GENIA Treebank@formal@@1@S@In this study, we created transgenic mice overexpressing ICSAT in lymphocytes.@@@@1@13@@oe@16-12-2010 1040377004@GENIA Treebank@formal@@1@S@Although spontaneous tumorigenesis was not observed, IL-2 production with Concanavalin A stimulation was significantly increased in transgenic mice overexpressing ICSAT.@@@@1@22@@oe@16-12-2010 1040377005@GENIA Treebank@formal@@1@S@ICSAT overexpression in lymphocytes seems insufficient for the leukemogenesis of ATL or multiple myeloma (MM), however, it may regulate T cell activation and its overexpression may lead to leukemogenesis via controlling IL-2 production.@@@@1@38@@oe@16-12-2010 1040377006@GENIA Treebank@formal@@1@S@Copyright 1999 Academic Press.@@@@1@5@@oe@16-12-2010 1040758001@GENIA Treebank@formal@@1@S@Clonality analysis of granulocytes and T lymphocytes in healthy females by the PCR-based HUMARA method.@@@@1@16@@oe@16-12-2010 1040758002@GENIA Treebank@formal@@1@S@Clonality analysis utilizing X-chromosome inactivation has been used in the study of various diseases, including hematological malignancies.@@@@1@19@@oe@16-12-2010 1040758003@GENIA Treebank@formal@@1@S@The human androgen receptor gene (HUMARA) assay is the newest of such methods, and the majority of the female population can be assessed by this relatively simple procedure.@@@@1@32@@oe@16-12-2010 1040758004@GENIA Treebank@formal@@1@S@One problem in using these clonality analysis methods, however, is that there may be significant variation in Lyonization in blood cells in normal individuals.@@@@1@27@@oe@16-12-2010 1040758005@GENIA Treebank@formal@@1@S@To determine the diversity in X-chromosome methylation patterns, which reflect Lyonization, assessed by the HUMARA assay in the supposedly normal population, we analyzed granulocytes and T cells from 97 relatively young (18- to 35-year-old) healthy female volunteers.@@@@1@43@@oe@16-12-2010 1040758006@GENIA Treebank@formal@@1@S@We found that the methylation patterns in the two HUMARA alleles were distributed even more widely, both in granuloctyes and in T cells, than previously reported with other methods.@@@@1@32@@oe@16-12-2010 1040758007@GENIA Treebank@formal@@1@S@We also found that the deviation of methylation in granulocytes and T cells was well correlated.@@@@1@17@@oe@16-12-2010 1040758008@GENIA Treebank@formal@@1@S@Thus, we conclude that appropriate controls from the same individuals, such as T cells in the case of stem cell disorders, should always be employed to conclusively determine whether certain cells of hematopoietic origin are clonal.@@@@1@40@@oe@16-12-2010 1040976301@GENIA Treebank@formal@@1@S@The Epstein-Barr virus oncoprotein latent membrane protein 1 engages the tumor necrosis factor receptor-associated proteins TRADD and receptor-interacting protein (RIP) but does not induce apoptosis or require RIP for NF-kappaB activation.@@@@1@34@@oe@16-12-2010 1040976302@GENIA Treebank@formal@@1@S@A site in the Epstein-Barr virus (EBV) transforming protein LMP1 that constitutively associates with the tumor necrosis factor receptor 1 (TNFR1)-associated death domain protein TRADD to mediate NF-kappaB and c-Jun N-terminal kinase activation is critical for long-term lymphoblastoid cell proliferation.@@@@1@46@@oe@16-12-2010 1040976303@GENIA Treebank@formal@@1@S@We now find that LMP1 signaling through TRADD differs from TNFR1 signaling through TRADD.@@@@1@15@@oe@16-12-2010 1040976304@GENIA Treebank@formal@@1@S@LMP1 needs only 11 amino acids to activate NF-kappaB or synergize with TRADD in NF-kappaB activation, while TNFR1 requires approximately 70 residues.@@@@1@24@@oe@16-12-2010 1040976305@GENIA Treebank@formal@@1@S@Further, LMP1 does not require TRADD residues 294 to 312 for NF-kappaB activation, while TNFR1 requires TRADD residues 296 to 302.@@@@1@24@@oe@16-12-2010 1040976306@GENIA Treebank@formal@@1@S@LMP1 is partially blocked for NF-kappaB activation by a TRADD mutant consisting of residues 122 to 293.@@@@1@18@@oe@16-12-2010 1040976307@GENIA Treebank@formal@@1@S@Unlike TNFR1, LMP1 can interact directly with receptor-interacting protein (RIP) and stably associates with RIP in EBV-transformed lymphoblastoid cell lines.@@@@1@24@@oe@16-12-2010 1040976308@GENIA Treebank@formal@@1@S@Surprisingly, LMP1 does not require RIP for NF-kappaB activation.@@@@1@11@@oe@16-12-2010 1040976309@GENIA Treebank@formal@@1@S@Despite constitutive association with TRADD or RIP, LMP1 does not induce apoptosis in EBV-negative Burkitt lymphoma or human embryonic kidney 293 cells.@@@@1@24@@oe@16-12-2010 1040976310@GENIA Treebank@formal@@1@S@These results add a different perspective to the molecular interactions through which LMP1, TRADD, and RIP participate in B-lymphocyte activation and growth.@@@@1@25@@oe@16-12-2010 1041100301@GENIA Treebank@formal@@1@S@Regulatory effects of interleukin-11 during acute lung inflammatory injury.@@@@1@10@@oe@16-12-2010 1041100302@GENIA Treebank@formal@@1@S@The role of interleukin-11 (IL-11) was evaluated in the IgG immune complex model of acute lung injury in rats.@@@@1@22@@oe@16-12-2010 1041100303@GENIA Treebank@formal@@1@S@IL-11 mRNA and protein were both up-regulated during the course of this inflammatory response.@@@@1@15@@oe@16-12-2010 1041100304@GENIA Treebank@formal@@1@S@Exogenously administered IL-11 substantially reduced, in a dose-dependent manner, the intrapulmonary accumulation of neutrophils and the lung vascular leak of albumin.@@@@1@24@@oe@16-12-2010 1041100305@GENIA Treebank@formal@@1@S@These in vivo anti-inflammatory effects of IL-11 were associated with reduced NF-kappaB activation in lung, reduced levels of tumor necrosis factor alpha (TNF-alpha) in bronchoalveolar lavage (BAL) fluids, and diminished up-regulation of lung vascular ICAM-1.@@@@1@42@@oe@16-12-2010 1041100306@GENIA Treebank@formal@@1@S@It is interesting that IL-11 did not affect BAL fluid content of the CXC chemokines, macrophage inflammatory protein-2 (MIP-2) and cytokine-inducible neutrophil chemoattractant (CINC); the presence of IL-11 did not affect these chemokines.@@@@1@40@@oe@16-12-2010 1041100307@GENIA Treebank@formal@@1@S@However, BAL content of C5a was reduced by IL-11.@@@@1@11@@oe@16-12-2010 1041100308@GENIA Treebank@formal@@1@S@These data indicate that IL-11 is a regulatory cytokine in the lung and that, like other members of this family, its anti-inflammatory properties appear to be linked to its suppression of NF-kappaB activation, diminished production of TNF-alpha, and reduced up-regulation of lung vascular ICAM-1.@@@@1@49@@oe@16-12-2010 1041100701@GENIA Treebank@formal@@1@S@ETS transcription factors regulate an enhancer activity in the third intron of TNF-alpha.@@@@1@14@@oe@16-12-2010 1041100702@GENIA Treebank@formal@@1@S@We describe an enhancer site in the third intron of tumor necrosis factor alpha (TNF-alpha).@@@@1@18@@oe@16-12-2010 1041100703@GENIA Treebank@formal@@1@S@A reporter construct containing the 5'-flanking region of the mouse TNF-alpha gene displayed weak activity when transfected into RAW264.7 macrophage-like cells.@@@@1@22@@oe@16-12-2010 1041100704@GENIA Treebank@formal@@1@S@The addition of the third intron of TNF-alpha to this construct resulted in an enhancement of CAT protein.@@@@1@19@@oe@16-12-2010 1041100705@GENIA Treebank@formal@@1@S@This enhancement was eliminated if a conserved 20-bp sequence was removed from the intron or if a dominant-negative ets-binding factor was co-transfected with the reporter gene.@@@@1@27@@oe@16-12-2010 1041100706@GENIA Treebank@formal@@1@S@Mutations of this site that destroyed potential ets transcription factor binding sites had reduced transcriptional activity.@@@@1@17@@oe@16-12-2010 1041100707@GENIA Treebank@formal@@1@S@The major transcription factor that bound to the oligonucleotide was confirmed to be GABP by supershift and competition analysis.@@@@1@20@@oe@16-12-2010 1041100708@GENIA Treebank@formal@@1@S@In RAW264.7 cells, the binding was constitutive, however, in bone marrow-derived macrophages binding activity was shown to be interferon-gamma inducible.@@@@1@24@@oe@16-12-2010 1041100709@GENIA Treebank@formal@@1@S@This may imply a role for ets transcription factors in the production of TNF-alpha.@@@@1@15@@oe@16-12-2010 1041507501@GENIA Treebank@formal@@1@S@Abnormal NF-kappa B activity in T lymphocytes from patients with systemic lupus erythematosus is associated with decreased p65-RelA protein expression.@@@@1@21@@oe@16-12-2010 1041507502@GENIA Treebank@formal@@1@S@Numerous cellular and biochemical abnormalities in immune regulation have been described in patients with systemic lupus erythematosus (SLE), including surface Ag receptor-initiated signaling events and lymphokine production.@@@@1@31@@oe@16-12-2010 1041507503@GENIA Treebank@formal@@1@S@Because NF-kappa B contributes to the transcription of numerous inflammatory genes and has been shown to be a molecular target of antiinflammatory drugs, we sought to characterize the functional role of the NF-kappa B protein complex in lupus T cells.@@@@1@42@@oe@16-12-2010 1041507504@GENIA Treebank@formal@@1@S@Freshly isolated T cells from lupus patients, rheumatoid arthritis (RA) patients, and normal individuals were activated physiologically via the TCR with anti-CD3 and anti-CD28 Abs to assess proximal membrane signaling, and with PMA and a calcium ionophore (A23187) to bypass membrane-mediated signaling events.@@@@1@51@@oe@16-12-2010 1041507505@GENIA Treebank@formal@@1@S@We measured the NF-kappa B binding activity in nuclear extracts by gel shift analysis.@@@@1@15@@oe@16-12-2010 1041507506@GENIA Treebank@formal@@1@S@When compared with normal cells, the activation of NF-kappa B activity in SLE patients was significantly decreased in SLE, but not in RA, patients.@@@@1@28@@oe@16-12-2010 1041507507@GENIA Treebank@formal@@1@S@NF-kappa B binding activity was absent in several SLE patients who were not receiving any medication, including corticosteroids.@@@@1@20@@oe@16-12-2010 1041507508@GENIA Treebank@formal@@1@S@Also, NF-kappa B activity remained absent in follow-up studies.@@@@1@11@@oe@16-12-2010 1041507509@GENIA Treebank@formal@@1@S@In supershift experiments using specific Abs, we showed that, in the group of SLE patients who displayed undetectable NF-kappa B activity, p65 complexes were not formed.@@@@1@30@@oe@16-12-2010 1041507510@GENIA Treebank@formal@@1@S@Finally, immunoblot analysis of nuclear extracts showed decreased or absent p65 protein levels.@@@@1@15@@oe@16-12-2010 1041507511@GENIA Treebank@formal@@1@S@As p65 complexes are transcriptionally active in comparison to the p50 homodimer, this novel finding may provide insight on the origin of abnormal cytokine or other gene transcription in SLE patients.@@@@1@33@@oe@16-12-2010