1007027401@GENIA Treebank@formal@@1@S@Nuclear factor-kappa B activity in T cells from patients with rheumatic diseases: a preliminary report.@@@@1@17@@oe@16-12-2010 1007027402@GENIA Treebank@formal@@1@S@OBJECTIVE: The NF-kappa B/Rel family of transcription factors regulates the expression of many genes involved in the immune or inflammatory response at the transcriptional level.@@@@1@27@@oe@16-12-2010 1007027403@GENIA Treebank@formal@@1@S@The aim of this study was to determine whether distinctive patterns of NF-kappa B activation are seen in different forms of joint disease.@@@@1@24@@oe@16-12-2010 1007027404@GENIA Treebank@formal@@1@S@METHODS: The DNA binding activity of these nucleoproteins was examined in purified synovial and peripheral T cells from patients with various chronic rheumatic diseases (12: four with rheumatoid arthritis; five with spondyloarthropathies; and three with osteoarthritis).@@@@1@43@@oe@16-12-2010 1007027405@GENIA Treebank@formal@@1@S@RESULTS: Electrophoretic mobility shift assays disclosed two specific complexes bound to a NF-kappa B specific 32P-labelled oligonucleotide in nucleoproteins extracted from purified T cells isolated from synovial fluid and peripheral blood of patients with rheumatoid arthritis.@@@@1@38@@oe@16-12-2010 1007027406@GENIA Treebank@formal@@1@S@The complexes consisted of p50/p50 homodimers and p50/p65 heterodimers.@@@@1@10@@oe@16-12-2010 1007027407@GENIA Treebank@formal@@1@S@Increased NF-kappa B binding to DNA in synovial T cells was observed relative to peripheral T cells.@@@@1@18@@oe@16-12-2010 1007027408@GENIA Treebank@formal@@1@S@In non-rheumatoid arthritis, binding of NF-kappa B in synovial T cells was exclusively mediated by p50/p50 homodimers.@@@@1@19@@oe@16-12-2010 1007027409@GENIA Treebank@formal@@1@S@CONCLUSION: Overall, the results suggest that NF-kappa B may play a central part in the activation of infiltrating T cells in chronic rheumatoid arthritis.@@@@1@27@@oe@16-12-2010 1007027410@GENIA Treebank@formal@@1@S@The activation of this nuclear factor is qualitatively different in rheumatoid synovial T cells to that in other forms of non-rheumatoid arthritis (for example, osteoarthritis, spondyloarthropathies).@@@@1@31@@oe@16-12-2010 1007095301@GENIA Treebank@formal@@1@S@High frequency of germ-line BRCA2 mutations among Hungarian male breast cancer patients without family history.@@@@1@16@@oe@16-12-2010 1007095302@GENIA Treebank@formal@@1@S@To determine the contribution of BRCA1 and BRCA2 mutations to the pathogenesis of male breast cancer in Hungary, the country with the highest male breast cancer mortality rates in continental Europe, a series of 18 male breast cancer patients and three patients with gynecomastia was analyzed for germ-line mutations in both BRCA1 and BRCA2.@@@@1@57@@oe@16-12-2010 1007095303@GENIA Treebank@formal@@1@S@Although no germ-line BRCA1 mutation was observed, 6 of the 18 male breast cancer cases (33%) carried truncating mutations in the BRCA2 gene.@@@@1@28@@oe@16-12-2010 1007095304@GENIA Treebank@formal@@1@S@Unexpectedly, none of them reported a family history for breast/ovarian cancer.@@@@1@13@@oe@16-12-2010 1007095305@GENIA Treebank@formal@@1@S@Four of six truncating mutations were novel, and two mutations were recurrent.@@@@1@14@@oe@16-12-2010 1007095306@GENIA Treebank@formal@@1@S@Four patients (22%) had a family history of breast/ovarian cancer in at least one first- or second-degree relative; however, no BRCA2 mutation was identified among them.@@@@1@32@@oe@16-12-2010 1007095307@GENIA Treebank@formal@@1@S@No mutation was identified in either of the genes in the gynecomastias.@@@@1@13@@oe@16-12-2010 1007095308@GENIA Treebank@formal@@1@S@These results provide evidence for a strong genetic component of male breast cancer in Hungary.@@@@1@16@@oe@16-12-2010 1007206801@GENIA Treebank@formal@@1@S@RFX-B is the gene responsible for the most common cause of the bare lymphocyte syndrome, an MHC class II immunodeficiency [published erratum appears in Immunity 1999 Mar;10(3):399]@@@@1@37@@oe@16-12-2010 1007206802@GENIA Treebank@formal@@1@S@The bare lymphocyte syndrome (BLS) is characterized by the absence of MHC class II transcription and humoral- and cellular-mediated immune responses to foreign antigens.@@@@1@27@@oe@16-12-2010 1007206803@GENIA Treebank@formal@@1@S@Three of the four BLS genetic complementation groups have defects in the activity of the MHC class II transcription factor RFX.@@@@1@22@@oe@16-12-2010 1007206804@GENIA Treebank@formal@@1@S@We have purified the RFX complex and sequenced its three subunits.@@@@1@12@@oe@16-12-2010 1007206805@GENIA Treebank@formal@@1@S@The sequence of the smallest subunit describes a novel gene, termed RFX-B.@@@@1@14@@oe@16-12-2010 1007206806@GENIA Treebank@formal@@1@S@RFX-B complements the predominant BLS complementation group (group B) and was found to be mutant in cell lines from this BLS group.@@@@1@25@@oe@16-12-2010 1007206807@GENIA Treebank@formal@@1@S@The protein has no known DNA-binding domain but does contain three ankyrin repeats that are likely to be important in protein-protein interactions.@@@@1@23@@oe@16-12-2010 1007207801@GENIA Treebank@formal@@1@S@Alternative polyadenylation events contribute to the induction of NF-ATc in effector T cells.@@@@1@14@@oe@16-12-2010 1007207802@GENIA Treebank@formal@@1@S@The transcription factor NF-ATc is synthesized in three prominent isoforms.@@@@1@11@@oe@16-12-2010 1007207803@GENIA Treebank@formal@@1@S@These differ in the length of their C terminal peptides and mode of synthesis.@@@@1@15@@oe@16-12-2010 1007207804@GENIA Treebank@formal@@1@S@Due to a switch from the use of a 3' polyA site to a more proximal polyA site, NF-ATc expression switches from the synthesis of the two longer isoforms in naive T cells to that of short isoform A in T effector cells.@@@@1@45@@oe@16-12-2010 1007207805@GENIA Treebank@formal@@1@S@The relative low binding affinity of cleavage stimulation factor CstF-64 to the proximal polyA site seems to contribute to its neglect in naive T cells.@@@@1@26@@oe@16-12-2010 1007207806@GENIA Treebank@formal@@1@S@These alternative polyadenylation events ensure the rapid accumulation of high concentrations of NF-ATc necessary to exceed critical threshold levels of NF-ATc for gene induction in effector T cells.@@@@1@29@@oe@16-12-2010 1007249701@GENIA Treebank@formal@@1@S@N-acetyl-L-cysteine inhibits primary human T cell responses at the dendritic cell level: association with NF-kappaB inhibition.@@@@1@18@@oe@16-12-2010 1007249702@GENIA Treebank@formal@@1@S@N-acetyl-L-cysteine (NAC) is an antioxidant molecule endowed with immunomodulatory properties.@@@@1@13@@oe@16-12-2010 1007249703@GENIA Treebank@formal@@1@S@To investigate the effect of NAC on the induction phase of T cell responses, we analyzed its action on human dendritic cells (DC) derived from adherent PBMC cultured with IL-4 and granulocyte-macrophage CSF.@@@@1@37@@oe@16-12-2010 1007249704@GENIA Treebank@formal@@1@S@We first found that NAC inhibited the constitutive as well as the LPS-induced activity of the transcription factor NF-kappaB.@@@@1@20@@oe@16-12-2010 1007249705@GENIA Treebank@formal@@1@S@In parallel, NAC was shown to down-regulate the production of cytokines by DC as well as their surface expression of HLA-DR, CD86 (B7-2), and CD40 molecules both at the basal state and upon LPS activation.@@@@1@41@@oe@16-12-2010 1007249706@GENIA Treebank@formal@@1@S@NAC also inhibited DC responses induced by CD40 engagement.@@@@1@10@@oe@16-12-2010 1007249707@GENIA Treebank@formal@@1@S@The inhibitory effects of NAC were not due to nonspecific toxicity as neither the viability of DC nor their mannose receptor-mediated endocytosis were modified by NAC.@@@@1@27@@oe@16-12-2010 1007249708@GENIA Treebank@formal@@1@S@Finally, we found that the addition of NAC to MLR between naive T cells and allogeneic DC resulted in a profound inhibition of alloreactive responses, which could be attributed to a defect of DC as APC-independent T cell responses were not inhibited by NAC.@@@@1@47@@oe@16-12-2010 1007249709@GENIA Treebank@formal@@1@S@Altogether, our results suggest that NAC might impair the generation of primary immune responses in humans through its inhibitory action on DC.@@@@1@24@@oe@16-12-2010 1007252901@GENIA Treebank@formal@@1@S@NF-ATc isoforms are differentially expressed and regulated in murine T and mast cells.@@@@1@14@@oe@16-12-2010 1007252902@GENIA Treebank@formal@@1@S@NF of activated T cells (NF-AT) denotes a family of transcription factors that regulate the activation-dependent expression of many immunologically important proteins.@@@@1@25@@oe@16-12-2010 1007252903@GENIA Treebank@formal@@1@S@At least four distinct genes encode the various family members, and several isoforms of these have been identified as well.@@@@1@22@@oe@16-12-2010 1007252904@GENIA Treebank@formal@@1@S@The overlapping expression patterns and similar in vitro binding and trans-activation activities on various promoter elements of NF-AT-regulated genes suggest some redundancy in the function of these proteins.@@@@1@29@@oe@16-12-2010 1007252905@GENIA Treebank@formal@@1@S@However, the phenotypic analysis of NF-AT-deficient mice supports the idea that there are tissue- and gene- specific functions as well.@@@@1@21@@oe@16-12-2010 1007252906@GENIA Treebank@formal@@1@S@In this study we have characterized the expression of NF-AT cDNAs in murine mast cells.@@@@1@16@@oe@16-12-2010 1007252907@GENIA Treebank@formal@@1@S@The majority of clones identified correspond to two NF-ATc isoforms that differ only in their amino-terminal sequence.@@@@1@18@@oe@16-12-2010 1007252908@GENIA Treebank@formal@@1@S@Despite minimal discrepancies in the coding region, there are striking tissue- and cell type-specific differences in isoform expression patterns.@@@@1@21@@oe@16-12-2010 1007252909@GENIA Treebank@formal@@1@S@Detection of NF-ATc.alpha mRNA is strictly dependent on cell activation signals in both T and mast cell lines.@@@@1@19@@oe@16-12-2010 1007252910@GENIA Treebank@formal@@1@S@In contrast, the beta isoform is expressed at very low constitutive levels in both cell types but is only up-regulated in response to mast cell activation signals delivered through the FcepsilonRI or via calcium ionophores.@@@@1@37@@oe@16-12-2010 1007252911@GENIA Treebank@formal@@1@S@These results demonstrate another level of regulation within the NF-AT family that can contribute to cell type-specific gene expression.@@@@1@20@@oe@16-12-2010 1007443201@GENIA Treebank@formal@@1@S@A direct interaction between the adaptor protein Cbl-b and the kinase zap-70 induces a positive signal in T cells.@@@@1@20@@oe@16-12-2010 1007443202@GENIA Treebank@formal@@1@S@Engagement of the T-cell receptor (TCR)-CD3 complex induces a rapid increase in the activities of Src-family and Syk/Zap-70-family kinases [1] [2].@@@@1@29@@oe@16-12-2010 1007443203@GENIA Treebank@formal@@1@S@These activated kinases then induce the tyrosine phosphorylation of multiple intracellular proteins, eventually leading to T-cell activation.@@@@1@19@@oe@16-12-2010 1007443204@GENIA Treebank@formal@@1@S@One of the prominent substrates for these kinases is the adaptor protein Cbl [3] and recent studies suggest that Cbl negatively regulates upstream kinases such as Syk and Zap-70 [4] [5].@@@@1@38@@oe@16-12-2010 1007443205@GENIA Treebank@formal@@1@S@Cbl-b, a homologue of Cbl, is widely expressed in many tissues and cells including hematopoietic cells [6] [7].@@@@1@25@@oe@16-12-2010 1007443206@GENIA Treebank@formal@@1@S@Cbl-b undergoes rapid tyrosine phosphorylation upon stimulation of the TCR and cytokine receptors [8] [9].@@@@1@20@@oe@16-12-2010 1007443207@GENIA Treebank@formal@@1@S@The role of Cbl-b is unclear, however.@@@@1@9@@oe@16-12-2010 1007443208@GENIA Treebank@formal@@1@S@Here, we show that overexpression of Cbl-b in T cells induced the constitutive activation of the transcription factor nuclear factor of activated T cells (NFAT).@@@@1@29@@oe@16-12-2010 1007443209@GENIA Treebank@formal@@1@S@A loss-of-function mutation in Cbl-b disrupted the interaction between Cbl-b and Zap-70 and nearly completely abrogated the Cbl-b-mediated activation of NFAT.@@@@1@22@@oe@16-12-2010 1007443210@GENIA Treebank@formal@@1@S@Unlike the proposed role of Cbl as a negative regulator, our results suggest that the Cbl homologue Cbl-b has a positive role in T-cell signaling, most likely via a direct interaction with the upstream kinase Zap-70.@@@@1@39@@oe@16-12-2010 1007564501@GENIA Treebank@formal@@1@S@Bacterial lipopolysaccharide activates nuclear factor-kappaB through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes.@@@@1@19@@oe@16-12-2010 1007564502@GENIA Treebank@formal@@1@S@Bacterial lipopolysaccharide (LPS)-mediated immune responses, including activation of monocytes, macrophages, and endothelial cells, play an important role in the pathogenesis of Gram-negative bacteria-induced sepsis syndrome.@@@@1@33@@oe@16-12-2010 1007564503@GENIA Treebank@formal@@1@S@Activation of NF-kappaB is thought to be required for cytokine release from LPS-responsive cells, a critical step for endotoxic effects.@@@@1@22@@oe@16-12-2010 1007564504@GENIA Treebank@formal@@1@S@Here we investigated the role and involvement of interleukin-1 (IL-1) and tumor necrosis factor (TNF-alpha) signal transducer molecules in LPS signaling in human dermal microvessel endothelial cells (HDMEC) and THP-1 monocytic cells.@@@@1@39@@oe@16-12-2010 1007564505@GENIA Treebank@formal@@1@S@LPS stimulation of HDMEC and THP-1 cells initiated an IL-1 receptor-like NF-kappaB signaling cascade.@@@@1@15@@oe@16-12-2010 1007564506@GENIA Treebank@formal@@1@S@In transient cotransfection experiments, dominant negative mutants of the IL-1 signaling pathway, including MyD88, IRAK, IRAK2, and TRAF6 inhibited both IL-1- and LPS-induced NF-kappaB-luciferase activity.@@@@1@31@@oe@16-12-2010 1007564507@GENIA Treebank@formal@@1@S@LPS-induced NF-kappaB activation was not inhibited by a dominant negative mutant of TRAF2 that is involved in TNF signaling.@@@@1@20@@oe@16-12-2010 1007564508@GENIA Treebank@formal@@1@S@LPS-induced activation of NF-kappaB-responsive reporter gene was not inhibited by IL-1 receptor antagonist.@@@@1@14@@oe@16-12-2010 1007564509@GENIA Treebank@formal@@1@S@TLR2 and TLR4 were expressed on the cell surface of HDMEC and THP-1 cells.@@@@1@15@@oe@16-12-2010 1007564510@GENIA Treebank@formal@@1@S@These findings suggest that a signal transduction molecule in the LPS receptor complex may belong to the IL-1 receptor/toll-like receptor (TLR) super family, and the LPS signaling cascade uses an analogous molecular framework for signaling as IL-1 in mononuclear phagocytes and endothelial cells.@@@@1@47@@oe@16-12-2010 1007587301@GENIA Treebank@formal@@1@S@Detection of intracellular phosphorylated STAT-1 by flow cytometry.@@@@1@9@@oe@16-12-2010 1007587302@GENIA Treebank@formal@@1@S@We have applied flow cytometry to the investigation of interferon-gamma activation of human monocytes.@@@@1@15@@oe@16-12-2010 1007587303@GENIA Treebank@formal@@1@S@This approach uses monoclonal antibodies that distinguish between the native and phosphorylated forms of STAT-1.@@@@1@16@@oe@16-12-2010 1007587304@GENIA Treebank@formal@@1@S@It enables rapid and quantitative assessment of STAT-1 phosphorylation on a discrete cell basis and is both more sensitive and less time consuming than immunoblotting.@@@@1@26@@oe@16-12-2010 1007587305@GENIA Treebank@formal@@1@S@Furthermore, it allows for discrimination between a mixture of cells that differ in their response to interferon-gamma.@@@@1@19@@oe@16-12-2010 1007587306@GENIA Treebank@formal@@1@S@This approach should allow for the evaluation of different intracellular signaling pathways using a combination of monoclonal reagents that are specific for native and activation modified proteins.@@@@1@28@@oe@16-12-2010 1007587307@GENIA Treebank@formal@@1@S@Application of this form of testing should prove valuable in screening for signaling defects in selected patients with recurrent infections.@@@@1@21@@oe@16-12-2010 1007587308@GENIA Treebank@formal@@1@S@In addition, this technique should permit dissection of a full range of cellular signaling pathways at the protein level.@@@@1@21@@oe@16-12-2010 1007715601@GENIA Treebank@formal@@1@S@Glucocorticoid hormone suppression of human neutrophil-mediated tumor cell cytostasis.@@@@1@10@@oe@16-12-2010 1007715602@GENIA Treebank@formal@@1@S@In the present study, we have investigated the effect of glucocorticoid hormones on neutrophil-mediated tumor cell cytostasis and found that hydrocortisone and a synthetic hormone, dexamethasone (Dex), inhibited cytostasis in the presence or absence of tumor necrosis factor-alpha.@@@@1@44@@oe@16-12-2010 1007715603@GENIA Treebank@formal@@1@S@The effect of Dex was completely reversed by a glucocorticoid receptor antagonist, RU38486.@@@@1@15@@oe@16-12-2010 1007715604@GENIA Treebank@formal@@1@S@To clarify the underlying mechanisms, we examined effects of Dex on the binding avidity of beta2 integrin on the neutrophil surface and how these might in turn affect neutrophil-to-tumor cell binding.@@@@1@33@@oe@16-12-2010 1007715605@GENIA Treebank@formal@@1@S@Dex was found to inhibit these neutrophil properties, and RU38486 completely suppressed both forms of Dex inhibition.@@@@1@19@@oe@16-12-2010 1007715606@GENIA Treebank@formal@@1@S@Taken together, our findings suggest that glucocorticoid hormone inhibition of neutrophil-mediated tumor cell cytostasis is at least partially due to a lowering of the ligand binding avidity of beta2 integrin on the neutrophil surface.@@@@1@36@@oe@16-12-2010 1007850201@GENIA Treebank@formal@@1@S@Abnormalities of cyclic adenosine monophosphate signaling in platelets from untreated patients with bipolar disorder.@@@@1@15@@oe@16-12-2010 1007850202@GENIA Treebank@formal@@1@S@BACKGROUND: Abnormalities in the cyclic adenosine monophosphate (cAMP)-dependent phosphorylation system have been recently reported in patients with bipolar disorder.@@@@1@24@@oe@16-12-2010 1007850203@GENIA Treebank@formal@@1@S@We evaluated the immunoreactivity of the regulatory and catalytic subunits of cAMP-dependent protein kinase (protein kinase A) and 1 of its substrates, Rap1, in platelets from untreated euthymic, manic, and depressed patients with bipolar disorder and healthy subjects.@@@@1@45@@oe@16-12-2010 1007850204@GENIA Treebank@formal@@1@S@METHODS: Platelets were collected from 112 drug-free patients with bipolar disorder (52 euthymic, 29 depressed, and 31 manic) and 62 healthy subjects.@@@@1@28@@oe@16-12-2010 1007850205@GENIA Treebank@formal@@1@S@The levels of cAMP-dependent protein kinase and Rap1 were assessed by Western blot analysis, immunostaining, and computer-assisted imaging.@@@@1@21@@oe@16-12-2010 1007850206@GENIA Treebank@formal@@1@S@RESULTS: The immunolabeling of the catalytic subunit of cAMP-dependent protein kinase was significantly different among groups (P<.001), with higher values in untreated depressed and manic patients with bipolar disorder compared with untreated euthymic patients with bipolar disorder and healthy subjects.@@@@1@47@@oe@16-12-2010 1007850207@GENIA Treebank@formal@@1@S@No significant differences were found in the immunolabeling of the regulatory subunits (type I and type II) of cAMP-dependent protein kinase.@@@@1@24@@oe@16-12-2010 1007850208@GENIA Treebank@formal@@1@S@The immunolabeling of Rap1 was significantly higher (P<.001) in untreated euthymic, depressed, and manic patients than in healthy persons.@@@@1@26@@oe@16-12-2010 1007850209@GENIA Treebank@formal@@1@S@CONCLUSIONS: Levels of Rap1 and the catalytic subunit of cAMP-dependent protein kinase are altered in the platelets of bipolar patients.@@@@1@22@@oe@16-12-2010 1007850210@GENIA Treebank@formal@@1@S@These findings may provide clues toward understanding the involvement of cAMP signaling in the pathogenesis of bipolar disorder.@@@@1@19@@oe@16-12-2010 1007910601@GENIA Treebank@formal@@1@S@Selective activation and functional significance of p38alpha mitogen-activated protein kinase in lipopolysaccharide-stimulated neutrophils.@@@@1@14@@oe@16-12-2010 1007910602@GENIA Treebank@formal@@1@S@Activation of leukocytes by proinflammatory stimuli selectively initiates intracellular signal transduction via sequential phosphorylation of kinases.@@@@1@17@@oe@16-12-2010 1007910603@GENIA Treebank@formal@@1@S@Lipopolysaccharide (LPS) stimulation of human neutrophils is known to result in activation of p38 mitogen-activated protein kinase (MAPk); however, the upstream activator(s) of p38 MAPk is unknown, and consequences of p38 MAPk activation remain largely undefined.@@@@1@47@@oe@16-12-2010 1007910604@GENIA Treebank@formal@@1@S@We investigated the MAPk kinase (MKK) that activates p38 MAPk in response to LPS, the p38 MAPk isoforms that are activated as part of this pathway, and the functional responses affected by p38 MAPk activation.@@@@1@40@@oe@16-12-2010 1007910605@GENIA Treebank@formal@@1@S@Although MKK3, MKK4, and MKK6 all activated p38 MAPk in experimental models, only MKK3 was found to activate recombinant p38 MAPk in LPS-treated neutrophils.@@@@1@28@@oe@16-12-2010 1007910606@GENIA Treebank@formal@@1@S@Of p38 MAPk isoforms studied, only p38alpha and p38delta were detected in neutrophils.@@@@1@15@@oe@16-12-2010 1007910607@GENIA Treebank@formal@@1@S@LPS stimulation selectively activated p38alpha.@@@@1@6@@oe@16-12-2010 1007910608@GENIA Treebank@formal@@1@S@Specific inhibitors of p38alpha MAPk blocked LPS-induced adhesion, nuclear factor-kappa B (NF-kappaB) activation, and synthesis of tumor necrosis factor-alpha (TNF-alpha).@@@@1@27@@oe@16-12-2010 1007910609@GENIA Treebank@formal@@1@S@Inhibition of p38alpha MAPk resulted in a transient decrease in TNF-alpha mRNA accumulation but persistent loss of TNF-alpha synthesis.@@@@1@20@@oe@16-12-2010 1007910610@GENIA Treebank@formal@@1@S@These findings support a pathway by which LPS stimulation of neutrophils results in activation of MKK3, which in turn activates p38alpha MAPk, ultimately regulating adhesion, NF-kappaB activation, enhanced gene expression of TNF-alpha, and regulation of TNF-alpha synthesis.@@@@1@43@@oe@16-12-2010 1008053201@GENIA Treebank@formal@@1@S@Inhibition of IL-4-inducible gene expression in human monocytes by type I and type II interferons.@@@@1@16@@oe@16-12-2010 1008053202@GENIA Treebank@formal@@1@S@The Th2-type cytokines, interleukin-4 (IL-4) and interleukin-13 (IL-13), induce expression of a distinct subset of genes in human monocytes, including FcepsilonRIIb (CD23), 15-lipoxygenase, IL-1 receptor antagonist (IL-1ra), and type I and type II IL-1 receptors (IL-1R).@@@@1@53@@oe@16-12-2010 1008053203@GENIA Treebank@formal@@1@S@Type I interferons (IFN-alpha and IFN-beta) and type II interferon (IFN-gamma) inhibit induction of these genes by IL-4 and IL-13.@@@@1@25@@oe@16-12-2010 1008053204@GENIA Treebank@formal@@1@S@However, the mechanism by which IFNs mediate this inhibition has not been defined.@@@@1@15@@oe@16-12-2010 1008053205@GENIA Treebank@formal@@1@S@In this overview, we discuss the role of the transcription factor, STAT6 (signal transducer and activator of transcription-6) in mediating IL-4- and IL-13-induced gene expression in monocytes.@@@@1@32@@oe@16-12-2010 1008053206@GENIA Treebank@formal@@1@S@We also discuss our recent findings that type I and type II IFNs suppress IL-4/IL-13-inducible gene expression by inhibiting tyrosine phosphorylation and nuclear translocation of STAT6.@@@@1@27@@oe@16-12-2010 1008053207@GENIA Treebank@formal@@1@S@The ability of type I and type II IFNs to inhibit IL-4/IL-13-induced STAT6 activity is dose- and time-dependent, and is not unique to monocytes because IFNs induce the same effects in fibroblasts.@@@@1@34@@oe@16-12-2010 1008053208@GENIA Treebank@formal@@1@S@Inhibition of STAT6 activity is not evident unless cells are preincubated with IFN for at least 1 h before IL-4 stimulation.@@@@1@22@@oe@16-12-2010 1008053209@GENIA Treebank@formal@@1@S@Furthermore, inhibition can be blocked by actinomycin D, indicating a requirement for de novo transcription.@@@@1@18@@oe@16-12-2010 1008053210@GENIA Treebank@formal@@1@S@We propose a model in which stimulation of monocytes by IFN activates de novo synthesis of an inhibitory factor, possibly one or more members of the SOCS/ SSI/CIS gene family, capable of suppressing activation of STAT6 by IL-4 and IL-13.@@@@1@42@@oe@16-12-2010 1008053211@GENIA Treebank@formal@@1@S@Because STAT6 activation plays an essential role in IL-4/IL-13-induced gene expression, the ability of IFN-beta and IFN-gamma to inhibit STAT6 activity provides an explanation for how IFNs can suppress IL-4/IL-13-inducible gene expression.@@@@1@34@@oe@16-12-2010 1008054401@GENIA Treebank@formal@@1@S@Lineage-specific activation of STAT3 by interferon-gamma in human neutrophils.@@@@1@10@@oe@16-12-2010 1008054402@GENIA Treebank@formal@@1@S@Binding of interferon-gamma (IFN-gamma) to its heterodimeric receptor induces activation of the tyrosine kinases JAK1 and JAK2 followed by tyrosine phosphorylation of STAT1alpha.@@@@1@26@@oe@16-12-2010 1008054403@GENIA Treebank@formal@@1@S@Selective activation of STAT1alpha at the IFN-gamma receptor is achieved by specific interaction between a cytosolic tyrosine motif including Y440 in the IFN-gamma receptor alpha-chain and the SH2 domain of STAT1alpha.@@@@1@32@@oe@16-12-2010 1008054404@GENIA Treebank@formal@@1@S@We demonstrate that, in addition to STAT1alpha, STAT3 is also activated by IFN-gamma in human neutrophils.@@@@1@19@@oe@16-12-2010 1008054405@GENIA Treebank@formal@@1@S@The activation of STAT3 was not found in human eosinophils, monocytes, and HL-60 cells, although the STAT3 protein was expressed in these cells.@@@@1@27@@oe@16-12-2010 1008054406@GENIA Treebank@formal@@1@S@The cell type-specific activation of STAT3 by IFN-gamma was also observed in neutrophils that are differentiated in vitro from human CD34+ hematopoietic stem cells.@@@@1@25@@oe@16-12-2010 1008054407@GENIA Treebank@formal@@1@S@These results indicate that a single cytokine receptor can activate different STAT family members in a cell-specific manner, which might result in cell-specific gene transcription.@@@@1@27@@oe@16-12-2010 1008087501@GENIA Treebank@formal@@1@S@Involvement of NF-kappaB p50/p65 heterodimer in activation of the human pro-interleukin-1beta gene at two subregions of the upstream enhancer element.@@@@1@21@@oe@16-12-2010 1008087502@GENIA Treebank@formal@@1@S@A region between-3134 and -2729 bp upstream from the transcription site of the human pro-interleukin 1beta (proIL-1beta) gene was identified as an LPS-responsive enhancer element.@@@@1@29@@oe@16-12-2010 1008087503@GENIA Treebank@formal@@1@S@In this study, the influence of the sequences located between -3134 and -2987 on the transcriptional activity of the proIL-1beta gene in LPS-stimulated Raw 264.7 cells was examined in detail.@@@@1@32@@oe@16-12-2010 1008087504@GENIA Treebank@formal@@1@S@The results obtained by transient transfection of fos -CAT constructs that contained serial 5'-deletion mutations showed that the region between -3134 and -3059 appears to be required for the induction of transcription by LPS.@@@@1@34@@oe@16-12-2010 1008087505@GENIA Treebank@formal@@1@S@Gel shift assay studies with synthetic oligonucleotides corresponding to partial sequences of the latter region and nuclear extracts from stimulated cells revealed specific protein binding sites between -3110 and -3090 and between -3079 and -3059.@@@@1@36@@oe@16-12-2010 1008087506@GENIA Treebank@formal@@1@S@These specific bindings were time and LPS dose dependent.@@@@1@10@@oe@16-12-2010 1008087507@GENIA Treebank@formal@@1@S@The results of supershift analysis using specific antibodies against transcription factors suggested that both binding complexes contained the NF-kappaB components p50 and p65, and did not contain other NF-kappaB proteins (p52, c-Rel, Rel B), AP-1 proteins (c-Fos, C-Jun), CREB or C/EBPbeta (NF-IL6).@@@@1@55@@oe@16-12-2010 1008087508@GENIA Treebank@formal@@1@S@Mutation of either of the putative NF-kappaB-binding sites in the enhancer element decreased the LPS-stimulated transcriptional activity.@@@@1@18@@oe@16-12-2010 1008087509@GENIA Treebank@formal@@1@S@These data indicated that two NF-kappaB-binding sites, which are located between -3134 and -3059, are critical for the activation of proIL-1beta gene transcription.@@@@1@26@@oe@16-12-2010 1008087510@GENIA Treebank@formal@@1@S@Copyright 1999 Academic Press.@@@@1@5@@oe@16-12-2010 1008090801@GENIA Treebank@formal@@1@S@Analysis of the modulation of transcriptional activity in myelopoiesis and leukemogenesis.@@@@1@12@@oe@16-12-2010 1008090802@GENIA Treebank@formal@@1@S@Acute myeloid leukemia (AML) is still associated with a mortality of 60 to 80%.@@@@1@18@@oe@16-12-2010 1008090803@GENIA Treebank@formal@@1@S@AML is characterized by a block in myeloid differentiation.@@@@1@10@@oe@16-12-2010 1008090804@GENIA Treebank@formal@@1@S@The transcription factors PU.1 and C/EBPalpha are responsible for normal myeloid differentiation from stem cells to monocytes or granulocytes.@@@@1@20@@oe@16-12-2010 1008090805@GENIA Treebank@formal@@1@S@In particular, PU.1 induces expression of the macrophage colony-stimulating factor (M-CSF) receptor and the development of monocytes, whereas C/EBPalpha increases the expression of the granulocyte colony-stimulating factor (G-CSF) receptor and leads to mature granulocytes.@@@@1@41@@oe@16-12-2010 1008090806@GENIA Treebank@formal@@1@S@In AML, chromosomal aberrations result in oncoproteins such as AML1/ETO, PML/RARalpha, or activated Ras, which can deregulate genes important for normal myelopoiesis.@@@@1@27@@oe@16-12-2010 1008090807@GENIA Treebank@formal@@1@S@Thus, AML1/ETO can bind to the transcription factor C/EBPalpha, inhibit C/EBPalpha-dependent transcription, and block granulocytic differentiation.@@@@1@20@@oe@16-12-2010 1008090808@GENIA Treebank@formal@@1@S@However, AML1/ETO can also synergize with the transcription factor AML1 to enhance the activity of the M-CSF receptor promoter.@@@@1@21@@oe@16-12-2010 1008090809@GENIA Treebank@formal@@1@S@On the other hand, the PML/RARalpha fusion protein causes transcriptional repression by recruiting the nuclear corepressor (N-CoR) histone deacetylase complex to the DNA, which results in decreased histone acetylation and a repressive chromatin organization.@@@@1@39@@oe@16-12-2010 1008090810@GENIA Treebank@formal@@1@S@Here we describe methods to investigate whether and how signaling agonists induce myeloid differentiation and how oncoproteins might cause AML by modulating the activity of transcription factors that are pivotal for normal myeloid development.@@@@1@35@@oe@16-12-2010 1008090811@GENIA Treebank@formal@@1@S@Copyright 1999 Academic Press.@@@@1@5@@oe@16-12-2010 1008094801@GENIA Treebank@formal@@1@S@Phosphorylation of TRAF2 inhibits binding to the CD40 cytoplasmic domain.@@@@1@11@@oe@16-12-2010 1008094802@GENIA Treebank@formal@@1@S@TRAF2 is a signal transducing adaptor molecule which binds to the CD40 cytoplasmic domain.@@@@1@15@@oe@16-12-2010 1008094803@GENIA Treebank@formal@@1@S@We have found that it is phosphorylated, predominantly on serine residues, when transiently overexpressed in 293 cells.@@@@1@20@@oe@16-12-2010 1008094804@GENIA Treebank@formal@@1@S@The phosphorylation appears to be related to the signaling events that are activated by TRAF2 under these circumstances, since two nonfunctional mutants were found to be phosphorylated significantly less than the wild-type protein.@@@@1@35@@oe@16-12-2010 1008094805@GENIA Treebank@formal@@1@S@Furthermore, the phosphorylation status of TRAF2 had significant effects on the ability of the protein to bind to CD40, as evidenced by our observations that the CD40 cytoplasmic domain interacted preferentially with underphosphorylated TRAF2 and that phosphatase treatment significantly enhanced the binding of TRAF2 to CD40.@@@@1@49@@oe@16-12-2010 1008094806@GENIA Treebank@formal@@1@S@We conclude from these studies that the phosphorylation of TRAF2 is likely to play an important role in regulating signaling by virtue of its ability to influence the CD40-TRAF2 interaction.@@@@1@31@@oe@16-12-2010 1008094807@GENIA Treebank@formal@@1@S@Copyright 1999 Academic Press.@@@@1@5@@oe@16-12-2010 1008213401@GENIA Treebank@formal@@1@S@Cobalt chloride-induced signaling in endothelium leading to the augmented adherence of sickle red blood cells and transendothelial migration of monocyte-like HL-60 cells is blocked by PAF-receptor antagonist.@@@@1@28@@oe@16-12-2010 1008213402@GENIA Treebank@formal@@1@S@In response to hypoxia, sickle red blood cells (SS RBC) and leukocytes exhibit increased adherence to the vascular endothelium, while diapedesis of leukocytes through the blood vessel increases.@@@@1@33@@oe@16-12-2010 1008213403@GENIA Treebank@formal@@1@S@However, the cellular signaling pathway(s) caused by hypoxia is poorly understood.@@@@1@16@@oe@16-12-2010 1008213404@GENIA Treebank@formal@@1@S@We utilized CoCl2 as a mimetic molecule for hypoxia to study cellular signaling pathways.@@@@1@15@@oe@16-12-2010 1008213405@GENIA Treebank@formal@@1@S@We found that in human umbilical vein endothelial cells (HUVEC), CoCl2 at 2 mM concentration induced the surface expression of a subset of CAMs (VCAM-1) and activation of transcription factor NF-kappaB in the nuclear extracts of HUVEC.@@@@1@43@@oe@16-12-2010 1008213406@GENIA Treebank@formal@@1@S@Furthermore, CoCl2 also caused time-dependent tyrosine phosphorylation of mitogen-activated protein (MAP) kinase isoform ERK2 without significantly affecting ERK1, indicating ERK2 is the preferred substrate for upstream kinase of the MAPK pathway.@@@@1@36@@oe@16-12-2010 1008213407@GENIA Treebank@formal@@1@S@Inhibitors of MAP kinase (PD98059) or platelet-activating factor (PAF)- receptor antagonist (CV3988) inhibited the CoCl2-induced NF-kappaB activation and VCAM-1 expression.@@@@1@27@@oe@16-12-2010 1008213408@GENIA Treebank@formal@@1@S@Augmented expression of VCAM-1 led to increased SS RBC adhesion, inhibitable by a VCAM-1 antibody.@@@@1@17@@oe@16-12-2010 1008213409@GENIA Treebank@formal@@1@S@Additionally, CoCl2 caused a two- to threefold increase in the rate of transendothelial migration of monocyte-like HL-60 cells and a twentyfold increase in phosphorylation of platelet endothelial cell adhesion molecules (PECAM-1).@@@@1@35@@oe@16-12-2010 1008213410@GENIA Treebank@formal@@1@S@The transendothelial migration of monocytes was inhibited by an antibody to PECAM-1.@@@@1@13@@oe@16-12-2010 1008213411@GENIA Treebank@formal@@1@S@Both phosphorylation of PECAM-1 and transendothelial migration of monocytes in response to CoCl2 were inhibited by protein kinase inhibitor (GF109203X) and augmented by protein phosphatase inhibitor (Calyculin A).@@@@1@33@@oe@16-12-2010 1008213412@GENIA Treebank@formal@@1@S@Our data suggests that CoCl2-induced cellular signals directing increased expression of VCAM-1 in HUVEC involve downstream activation of MAP kinase and NF-kappaB, while the phosphorylation of PECAM-1 occurs as a result of activation of PKC.@@@@1@37@@oe@16-12-2010 1008213413@GENIA Treebank@formal@@1@S@We conclude that PAF-receptor antagonist inhibits the CoCl2- or hypoxia-induced increase in the adhesion of SS RBC, PECAM-1 phosphorylation, and the concomitant transendothelial migration of monocytes.@@@@1@29@@oe@16-12-2010 1008243601@GENIA Treebank@formal@@1@S@Impaired binding of a DQ2 and DQ8-binding HSV VP16 peptide to a DQA1*0501/DQB1*0302 trans class II heterodimer.@@@@1@18@@oe@16-12-2010 1008243602@GENIA Treebank@formal@@1@S@DQalpha and DQbeta trans heterodimeric HLA-DQ molecules form in individuals heterozygous for the DQ2 and DQ8 specificities.@@@@1@18@@oe@16-12-2010 1008243603@GENIA Treebank@formal@@1@S@Unique functions and disease associations have been postulated for such trans-dimers, which may be different from cis-encoded DQ molecules encoded by the corresponding haplotypes.@@@@1@26@@oe@16-12-2010 1008243604@GENIA Treebank@formal@@1@S@We analyzed the ability of the trans-dimer encoded by HLA-DQA1*0501/DQB1*0302 to bind a peptide antigen which interacts with DQ molecules encoded by both parental haplotypes.@@@@1@26@@oe@16-12-2010 1008243605@GENIA Treebank@formal@@1@S@Markedly impaired binding was observed, consistent with both the use of different anchor residues and with changes in levels of DQ cis-dimer availability for peptide binding interactions.@@@@1@29@@oe@16-12-2010 1008247301@GENIA Treebank@formal@@1@S@Molecular mechanisms of neutrophil-endothelial cell adhesion induced by redox imbalance.@@@@1@11@@oe@16-12-2010 1008247302@GENIA Treebank@formal@@1@S@Previous studies have implicated a role for intracellular thiols in the activation of nuclear factor-kappaB and transcriptional regulation of endothelial cell adhesion molecules.@@@@1@24@@oe@16-12-2010 1008247303@GENIA Treebank@formal@@1@S@This study was designed to determine whether changes in endothelial cell glutathione (GSH) or oxidized glutathione (GSSG) can alter neutrophil adhesivity and to define the molecular mechanism that underlies this GSSG/GSH-induced adhesion response.@@@@1@38@@oe@16-12-2010 1008247304@GENIA Treebank@formal@@1@S@Treatment of human umbilical vein endothelial cell (HUVEC) monolayers for 6 hours with 0.2 mmol/L diamide and 1 mmol/L buthionine sulfoximine (BSO) decreased GSH levels and increased the ratio of GSSG to GSH without cell toxicity.@@@@1@41@@oe@16-12-2010 1008247305@GENIA Treebank@formal@@1@S@These redox changes are similar to those observed with anoxia/reoxygenation.@@@@1@11@@oe@16-12-2010 1008247306@GENIA Treebank@formal@@1@S@Diamide plus BSO-induced thiol/disulfide imbalance was associated with a biphasic increase in neutrophil adhesion to HUVECs with peak responses observed at 15 minutes (phase 1) and 240 minutes (phase 2).@@@@1@35@@oe@16-12-2010 1008247307@GENIA Treebank@formal@@1@S@N-Acetylcysteine treatment attenuated neutrophil adhesion in both phases, which indicated a role for GSH in the adhesion responses.@@@@1@20@@oe@16-12-2010 1008247308@GENIA Treebank@formal@@1@S@Interestingly, phase 1 adhesion was inversely correlated with GSH levels but not with the GSSG/GSH ratio, whereas phase 2 neutrophil adhesion was positively correlated with GSSG/GSH ratio but not with GSH levels.@@@@1@35@@oe@16-12-2010 1008247309@GENIA Treebank@formal@@1@S@Intercellular adhesion molecule-1 and P-selectin-specific monoclonal antibodies attenuated the increased neutrophil adhesion during both phases, whereas an anti-E-selectin monoclonal antibody also attenuated the phase 2 response.@@@@1@28@@oe@16-12-2010 1008247310@GENIA Treebank@formal@@1@S@Pretreatment with actinomycin D and cycloheximide or with competing ds-oligonucleotides that contained nuclear factor-kappaB or activator protein-1 cognate DNA sequences significantly attenuated the phase 2 response, which implicated a role for de novo protein synthesis.@@@@1@37@@oe@16-12-2010 1008247311@GENIA Treebank@formal@@1@S@Surface expression of intercellular adhesion molecule-1, P-selectin, and E-selectin on HUVECs correlated with the phase 1 and 2 neutrophil adhesion responses.@@@@1@24@@oe@16-12-2010 1008247312@GENIA Treebank@formal@@1@S@This study demonstrates that changes in endothelial cell GSSG/GSH cause transcription-independent and transcription-dependent surface expression of different endothelial cell adhesion molecules, which leads to a 2-phase neutrophil-endothelial adhesion response.@@@@1@31@@oe@16-12-2010 1008672501@GENIA Treebank@formal@@1@S@MDS1/EVI1 enhances TGF-beta1 signaling and strengthens its growth-inhibitory effect but the leukemia-associated fusion protein AML1/MDS1/EVI1, product of the t(3;21), abrogates growth-inhibition in response to TGF-beta1.@@@@1@28@@oe@16-12-2010 1008672502@GENIA Treebank@formal@@1@S@MDS1/EVI1, located on chromosome 3 band q26, encodes a zinc-finger DNA-binding transcription activator not detected in normal hematopoietic cells but expressed in several normal tissues.@@@@1@28@@oe@16-12-2010 1008672503@GENIA Treebank@formal@@1@S@MDS1/EVI1 is inappropriately activated in myeloid leukemias following chromosomal rearrangements involving band 3q26.@@@@1@14@@oe@16-12-2010 1008672504@GENIA Treebank@formal@@1@S@The rearrangements lead either to gene truncation, and to expression of the transcription repressor EVI1, as seen in the t(3;3)(q21;q26) and inv(3)(q21q26), or to gene fusion, as seen in the t(3;21)(q26;q22) which results in the fusion protein AML1/MDS1/EVI1.@@@@1@43@@oe@16-12-2010 1008672505@GENIA Treebank@formal@@1@S@This fusion protein contains the DNA-binding domain of the transcription factor AML1 fused in-frame to the entire MDS1/EVI1 with the exclusion of its first 12 amino acids.@@@@1@28@@oe@16-12-2010 1008672506@GENIA Treebank@formal@@1@S@In this report, we have analyzed the response of the hematopoietic precursor cell line 32Dcl3, expressing either the normal protein MDS1/EVI1 or the fusion protein AML1/MDS1/EVI1, to factors that control cell differentiation or cell replication.@@@@1@39@@oe@16-12-2010 1008672507@GENIA Treebank@formal@@1@S@The 32Dcl3 cells are IL-3-dependent for growth and they differentiate into granulocytes when exposed to G-CSF.@@@@1@17@@oe@16-12-2010 1008672508@GENIA Treebank@formal@@1@S@They are growth-inhibited by TGF-beta1.@@@@1@6@@oe@16-12-2010 1008672509@GENIA Treebank@formal@@1@S@We show that whereas the expression of MDS1/EVI1 has no effect on granulocytic differentiation induced by G-CSF, expression of AML1/MDS1/EVI1 blocks differentiation resulting in cell death.@@@@1@28@@oe@16-12-2010 1008672510@GENIA Treebank@formal@@1@S@This effect is similar to that previously described by others for 32Dcl3 cells that express transgenic Evil.@@@@1@18@@oe@16-12-2010 1008672511@GENIA Treebank@formal@@1@S@Furthermore, we show that whereas the expression of the fusion protein AML1/MDS1/EVI1 completely abrogates the growth-inhibitory effect of TGF-beta1 and allows 32Dcl3 cells to proliferate, expression of the normal protein MDS1/EVI1 has the opposite effect, and it strengthens the response of cells to the growth-inhibitory effect of TGF-beta1.@@@@1@52@@oe@16-12-2010 1008672512@GENIA Treebank@formal@@1@S@By using the yeast two-hybrid system, we also show that EVI1 (contained in its entirety in MDS1/EVI1 and AML1/MDS1/EVI1) physically interacts with SMAD3, which is an intracellular mediator of TGF-beta1 signaling.@@@@1@36@@oe@16-12-2010 1008672513@GENIA Treebank@formal@@1@S@Finally, we have correlated the response of the cells to G-CSF or TGF-beta1 with the ability of the normal and fusion proteins to activate or repress promoters which they can directly regulate by binding to the promoter site.@@@@1@40@@oe@16-12-2010 1008672514@GENIA Treebank@formal@@1@S@We propose that mutations of MDS1/EVI1 either by gene truncation resulting in the transcription repressor EVI1 or by gene fusion to AML1 lead to an altered cellular response to growth and differentiation factors that could result in leukemic transformation.@@@@1@40@@oe@16-12-2010 1008672515@GENIA Treebank@formal@@1@S@The different response of myeloid cells ectopically expressing the normal or the fusion protein to G-CSF and TGF-beta1 could depend on the different transactivation properties of these proteins resulting in divergent expression of downstream genes regulated by the two proteins.@@@@1@41@@oe@16-12-2010 1008718101@GENIA Treebank@formal@@1@S@Interferon-alpha induction of STATs1, -3 DNA binding and growth arrest is independent of Lck and active mitogen-activated kinase in T cells.@@@@1@23@@oe@16-12-2010 1008718102@GENIA Treebank@formal@@1@S@Type I interferons (IFNs) are a family of cytokines that have antiviral and antiproliferative effects.@@@@1@18@@oe@16-12-2010 1008718103@GENIA Treebank@formal@@1@S@Data regarding the processes by which these cytokines transduce signals from the cell membrane to the nucleus are becoming increasingly complex.@@@@1@22@@oe@16-12-2010 1008718104@GENIA Treebank@formal@@1@S@The most characterized pathway is via JAK-STAT signaling.@@@@1@9@@oe@16-12-2010 1008718105@GENIA Treebank@formal@@1@S@Previous studies established a potential role for the Src-family kinase Lck in JAK-STAT signaling.@@@@1@15@@oe@16-12-2010 1008718106@GENIA Treebank@formal@@1@S@Therefore, this study was designed to analyze the role of Lck in IFN-alpha signaling by using the Jurkat, JCam (an Lck-defective cell line derived from Jurkat), and JCam/Lck (JCam cells with Lck restored).@@@@1@41@@oe@16-12-2010 1008718107@GENIA Treebank@formal@@1@S@The results show that IFN-alpha can induce MAPK activity, but only in cells containing Lck.@@@@1@17@@oe@16-12-2010 1008718108@GENIA Treebank@formal@@1@S@Furthermore, STATs1 and -3 are effectively phosphorylated and activated to bind DNA in the absence of Lck expression in IFN-alpha-treated cells.@@@@1@23@@oe@16-12-2010 1008718109@GENIA Treebank@formal@@1@S@Finally, the results demonstrate that IFN-alpha exerts an antiproliferative effect in all three cell lines.@@@@1@17@@oe@16-12-2010 1008718110@GENIA Treebank@formal@@1@S@These data indicate that Lck and active MAPK do not affect IFN-alpha-induced growth arrest or induction of STAT1s1 and -3 DNA binding ability.@@@@1@24@@oe@16-12-2010 1008718111@GENIA Treebank@formal@@1@S@Copyright 1999 Academic Press.@@@@1@5@@oe@16-12-2010 1008718501@GENIA Treebank@formal@@1@S@Decreased proteasome-mediated degradation in T cells from the elderly: A role in immune senescence.@@@@1@16@@oe@16-12-2010 1008718502@GENIA Treebank@formal@@1@S@Induction of NFkappaB is a highly regulated process requiring phosphorylation, ubiquitination, and proteasome-mediated degradation of the cytosolic inhibitor IkappaBalpha.@@@@1@22@@oe@16-12-2010 1008718503@GENIA Treebank@formal@@1@S@Analyses of the regulation of IkappaBalpha in TNF-alpha-treated T lymphocytes from young and elderly donors revealed severely compromised degradation of IkappaBalpha in T cells from the elderly.@@@@1@28@@oe@16-12-2010 1008718504@GENIA Treebank@formal@@1@S@Examination of activation-induced phosphorylation and ubiquitination of IkappaBalpha did not demonstrate any significant age-related alterations.@@@@1@16@@oe@16-12-2010 1008718505@GENIA Treebank@formal@@1@S@However, examination of proteasome activity in these T cells using fluorogenic peptide assays revealed a significant age-related decline in chymotryptic activity.@@@@1@23@@oe@16-12-2010 1008718506@GENIA Treebank@formal@@1@S@These results suggest that a decline in proteasome activity results in a failure to fully degrade IkappaBalpha in the elderly.@@@@1@21@@oe@16-12-2010 1008718507@GENIA Treebank@formal@@1@S@This failure to degrade IkappaBalpha may underlie both the observed decrease in NFkappaB induction and the IL-2 receptor expression in TNF-treated T cells during aging.@@@@1@26@@oe@16-12-2010 1008718508@GENIA Treebank@formal@@1@S@Thus, decreased proteasome-mediated degradation may be central to immune dysfunction that accompanies aging.@@@@1@15@@oe@16-12-2010 1008718509@GENIA Treebank@formal@@1@S@Copyright 1999 Academic Press.@@@@1@5@@oe@16-12-2010 1008764801@GENIA Treebank@formal@@1@S@T helper differentiation proceeds through Stat1-dependent, Stat4-dependent and Stat4-independent phases.@@@@1@12@@oe@16-12-2010 1008764802@GENIA Treebank@formal@@1@S@Much of our focus in understanding Th1/Th2 development has been on the signals delivered by IL-12 and IL-4 as final determinants of terminal T cell differentiation.@@@@1@27@@oe@16-12-2010 1008764803@GENIA Treebank@formal@@1@S@Because extinction of IL-12 signaling in early Th2 development could potentially be important in imprinting a more permanent Th2 phenotype on a population of T cells, we have also examined various parameters regulating the IL-12 signaling pathway.@@@@1@39@@oe@16-12-2010 1008764804@GENIA Treebank@formal@@1@S@Whereas IL-4 appears to repress functional IL-12 signaling through inhibition of IL-12R beta 2 expression, IFN-gamma in the mouse, and IFN-alpha in the human appear to induce IL-12R beta 2 expression and promote IL-12 responsiveness.@@@@1@38@@oe@16-12-2010 1008764805@GENIA Treebank@formal@@1@S@We propose that Th1 development can be considered in two stages, capacitance and development.@@@@1@16@@oe@16-12-2010 1008764806@GENIA Treebank@formal@@1@S@Capacitance would simply involve expression of IL-12R beta 1 and beta 2 subunits, regulated by TCR, IL-4 and IFNs.@@@@1@22@@oe@16-12-2010 1008764807@GENIA Treebank@formal@@1@S@The second stage, development, we propose is the true IL-12 induced developmental stage, involving expression of Stat4 inducible proteins.@@@@1@23@@oe@16-12-2010 1008764808@GENIA Treebank@formal@@1@S@In the human, this may also occur via IFN-alpha, which is able to activate Stat4.@@@@1@18@@oe@16-12-2010 1008764809@GENIA Treebank@formal@@1@S@It is perhaps possible that all of Stat4 actions on Th1 development may be exert directly by Stat4 at the IFN-gamma gene, however we suggest that, more likely, Stat4 may act to induce Th1 development through the induction of other non-cytokine genes, whose stable expression maintains the transcriptional state of a Th1 cell.@@@@1@58@@oe@16-12-2010 1008799301@GENIA Treebank@formal@@1@S@Identification of upstream regulatory elements that repress expression of adult beta-like globin genes in a primitive erythroid environment.@@@@1@19@@oe@16-12-2010 1008799302@GENIA Treebank@formal@@1@S@Our investigations have focused on localizing cis-elements responsible for the down regulation of the adult beta-like globin genes (delta and beta) in immature, or primitive erythroid tissues.@@@@1@31@@oe@16-12-2010 1008799303@GENIA Treebank@formal@@1@S@We studied their activity after transfection into K562 cells, an erythroleukemia cell line with an embryonic-fetal phenotype.@@@@1@19@@oe@16-12-2010 1008799304@GENIA Treebank@formal@@1@S@Analyzed DNA sequences included delta and beta 5' flanking regions extending from approximately -500 to +50bp (promoter regions), truncated delta and beta 5' flanking regions extending from approximately -250 to +50 bp, and chimeric promoter constructions, which consisted of a distal delta or beta fragment fused to a proximal beta or delta sequence.@@@@1@59@@oe@16-12-2010 1008799305@GENIA Treebank@formal@@1@S@In CAT reporter constructions no appreciable level of CAT activity was supported by the beta globin promoter, and only low level activity by the delta promoter.@@@@1@28@@oe@16-12-2010 1008799306@GENIA Treebank@formal@@1@S@Truncation of the beta globin promoter led to a 2-3 fold increase in promoter activity.@@@@1@16@@oe@16-12-2010 1008799307@GENIA Treebank@formal@@1@S@In contrast, deletion of the upstream portion of the delta promoter led to a 10 fold decrease in expression.@@@@1@21@@oe@16-12-2010 1008799308@GENIA Treebank@formal@@1@S@Coupling of the upstream beta globin sequence from approximately -500 to -250 bp to the truncated delta promoter fragment led to complete extinction of transcription activity, consistent with a negative regulatory effect of the beta globin gene upstream element(s).@@@@1@44@@oe@16-12-2010 1008799309@GENIA Treebank@formal@@1@S@Fusion of the upstream portion of the delta promoter to the truncated beta globin promoter yielded a modest increase in promoter strength relative to the truncated beta gene promoter, indicating the presence of a positive transcriptional element(s) in the upstream delta globin regulatory region.@@@@1@49@@oe@16-12-2010 1008799310@GENIA Treebank@formal@@1@S@Site-directed mutagenesis of binding sites for the repressor proteins BP1 and BP2 in the upstream portion of the beta globin gene flanking region led to a 4-6 fold increase in promoter activity.@@@@1@33@@oe@16-12-2010 1008799311@GENIA Treebank@formal@@1@S@DNase I footprinting of the upstream delta-globin region revealed protected sequences corresponding to consensus binding sites for GATA-1 and BP2.@@@@1@21@@oe@16-12-2010 1008799312@GENIA Treebank@formal@@1@S@These results confirm that sequences in the upstream promoter region of the adult beta globin gene contribute to its factor-mediated suppression early in development and then may modulate its expression at a later stage.@@@@1@35@@oe@16-12-2010 1008914001@GENIA Treebank@formal@@1@S@Reduction of tumour necrosis factor alpha expression and signalling in peripheral blood mononuclear cells from patients with thalassaemia or sickle cell anaemia upon treatment with desferrioxamine.@@@@1@27@@oe@16-12-2010 1008914002@GENIA Treebank@formal@@1@S@Recent evidence indicates that the rate of progression of the HIV-1 disease is significantly reduced in thalassaemia major patients upon treatment with high doses of desferrioxamine (DFX).@@@@1@30@@oe@16-12-2010 1008914003@GENIA Treebank@formal@@1@S@The authors have previously demonstrated that in vitro exposure of mononuclear cells to DFX decreases the bioavailability of tumour necrosis factor alpha (TNF-alpha) which has a stimulatory effect on HIV-1 replication.@@@@1@34@@oe@16-12-2010 1008914004@GENIA Treebank@formal@@1@S@In this study, therefore, TNF-alpha bioavailability from mononuclear cells isolated from 10 patients with thalassaemia or sickle cell anaemia given DFX as compared to 10 untreated subjects has been evaluated.@@@@1@33@@oe@16-12-2010 1008914005@GENIA Treebank@formal@@1@S@Evidence is presented showing that DFX treatment reduces TNF-alpha bioavailability (P<0.05) by inhibiting its steady state (P<0.05) and by enhancing its inactivation through binding to soluble TNF-alpha receptor type II (P<0.05).@@@@1@44@@oe@16-12-2010 1008914006@GENIA Treebank@formal@@1@S@We also show that DFX treatment limits the in vivo activation of NF-kappaB, a transcription factor involved in both TNF-alpha gene transcription and TNF-alpha signalling (P<0.005).@@@@1@32@@oe@16-12-2010 1008914007@GENIA Treebank@formal@@1@S@We conclude that TNF-alpha bioavailability and signalling are impaired in patients upon DFX treatment.@@@@1@15@@oe@16-12-2010 1008914008@GENIA Treebank@formal@@1@S@This mechanism may contribute to delayed progression of the HIV-1 infection in vivo.@@@@1@14@@oe@16-12-2010 1008914009@GENIA Treebank@formal@@1@S@Copyright 1999 Academic Press.@@@@1@5@@oe@16-12-2010 1008956601@GENIA Treebank@formal@@1@S@Involvement of adenylate cyclase and p70(S6)-kinase activation in IL-10 up-regulation in human monocytes by gp41 envelope protein of human immunodeficiency virus type 1.@@@@1@24@@oe@16-12-2010 1008956602@GENIA Treebank@formal@@1@S@Our previous results show that recombinant gp41 (aa565-647), the extracellular domain of HIV-1 transmembrane glycoprotein, stimulates interleukin-10 (IL-10) production in human monocytes.@@@@1@29@@oe@16-12-2010 1008956603@GENIA Treebank@formal@@1@S@The signal cascade transducing this effect is not yet clear.@@@@1@11@@oe@16-12-2010 1008956604@GENIA Treebank@formal@@1@S@In this study, we examined whether gp41-induced IL-10 up-regulation is mediated by the previously described synergistic activation of cAMP and NF-kappaB pathways.@@@@1@24@@oe@16-12-2010 1008956605@GENIA Treebank@formal@@1@S@gp41 induced cAMP accumulation in monocytes in a time- and concentration-dependent manner and the adenylate cyclase inhibitor SQ 22536 suppressed gp41-induced IL-10 production in monocytes.@@@@1@26@@oe@16-12-2010 1008956606@GENIA Treebank@formal@@1@S@In contrast, gp41 failed to stimulate NF-kappaB binding activity in as much as no NF-kappaB bound to the main NF-kappaB-binding site 2 of the IL-10 promoter after addition of gp41.@@@@1@32@@oe@16-12-2010 1008956607@GENIA Treebank@formal@@1@S@We also examined the involvement of other signal transduction pathways.@@@@1@11@@oe@16-12-2010 1008956608@GENIA Treebank@formal@@1@S@Specific inhibitors of p70(S6)-kinase (rapamycin), and Gi protein (pertussis toxin), prevented induction of IL-10 production by gp41 in monocytes, while inhibitors of the phosphatidylinositol 3-kinase (PI 3-kinase) (wortmannin) and mitogen-activated protein kinase (MAPK) pathway (PD 98059) did not.@@@@1@54@@oe@16-12-2010 1008956609@GENIA Treebank@formal@@1@S@Thus HIV-1 gp41-induced IL-10 up-regulation in monocytes may not involve NF-kappaB, MAPK, or PI 3-kinase activation, but rather may operate through activation of adenylate cyclase and pertussis-toxin-sensitive Gi/Go protein to effect p70(S6)-kinase activation.@@@@1@37@@oe@16-12-2010 1008990701@GENIA Treebank@formal@@1@S@Estrone potentiates myeloid cell differentiation: a role for 17 beta-hydroxysteroid dehydrogenase in modulating hemopoiesis.@@@@1@16@@oe@16-12-2010 1008990702@GENIA Treebank@formal@@1@S@Hormones such as 1 alpha, 25-dihydroxy vitamin D3 (D3), all-trans retinoic acid, and 9-cis retinoic acid stimulate differentiation of myeloid progenitor cells via their interaction with specific hormone receptors.@@@@1@33@@oe@16-12-2010 1008990703@GENIA Treebank@formal@@1@S@However, the sensitivity of cells to these agents is not merely governed by the expression of their receptors and the availability of ligand to bind them.@@@@1@28@@oe@16-12-2010 1008990704@GENIA Treebank@formal@@1@S@Recent studies from our group suggested that the actions of D3 and retinoids on myelopoiesis also are influenced by endogenous mechanisms involving other steroid hormones.@@@@1@26@@oe@16-12-2010 1008990705@GENIA Treebank@formal@@1@S@In this study we examined the influence of local estrogen metabolism on the differentiation of HL60 cells and normal primitive myeloid progenitor cells.@@@@1@24@@oe@16-12-2010 1008990706@GENIA Treebank@formal@@1@S@Quantitative thin-layer chromatography (TLC) analyses showed that HL60 and normal cells are able to generate estrone (E1) from estradiol (E2).@@@@1@27@@oe@16-12-2010 1008990707@GENIA Treebank@formal@@1@S@Neither cell population generated significant amounts of E2 from E1.@@@@1@11@@oe@16-12-2010 1008990708@GENIA Treebank@formal@@1@S@Reverse transcriptase polymerase chain reaction and Northern analyses confirmed that normal and leukemic myeloid progenitor cells expressed mRNA for the type I and IV isoforms of 17 beta-hydroxysteroid dehydrogenase.@@@@1@30@@oe@16-12-2010 1008990709@GENIA Treebank@formal@@1@S@Conversion of E2 to E1 was upregulated within 24 hours when HL60 cells were treated with either all-trans retinoic acid or D3 at doses that induce their differentiation toward neutrophils or monocytes, respectively.@@@@1@35@@oe@16-12-2010 1008990710@GENIA Treebank@formal@@1@S@Similarly, D3-induced monocyte differentiation of normal myeloid progenitor cells was associated with increased capacity to generate E1 from E2.@@@@1@21@@oe@16-12-2010 1008990711@GENIA Treebank@formal@@1@S@When HL60 cells or normal myeloid progenitor cells were exposed to exogenous E1 they became more sensitive to the differentiation-inducing effects of D3.@@@@1@24@@oe@16-12-2010 1008990712@GENIA Treebank@formal@@1@S@Data presented provide further evidence for the local modulation of myelopoiesis by intracrine mechanisms.@@@@1@15@@oe@16-12-2010 1008990713@GENIA Treebank@formal@@1@S@In particular, our findings suggest that local metabolism of steroids by normal as well as leukemic myeloid cells influences their responsiveness to D3 and retinoids.@@@@1@27@@oe@16-12-2010 1009033801@GENIA Treebank@formal@@1@S@The relationship between Ca2+-ATPase and freely exchangeable Ca2+ in the dense tubules: a study in platelets from women.@@@@1@20@@oe@16-12-2010 1009033802@GENIA Treebank@formal@@1@S@The main aims of this work were to examine in women: the relationship between the freely exchangeable Ca2+ (FECa2+) in the dense tubules and the activity of the sarco(endo)plasmic reticulum (SER) Ca2+-ATPase (SERCA) in platelets, and the relationship of these parameters with blood pressure and serum lipoproteins.@@@@1@60@@oe@16-12-2010 1009033803@GENIA Treebank@formal@@1@S@Platelets from 14 white and 13 black women in good health were studied.@@@@1@14@@oe@16-12-2010 1009033804@GENIA Treebank@formal@@1@S@The FECa2+ was measured as the ionomycin-evoked Ca2+ release (in the presence of thapsigargin) in Ca2+-free medium.@@@@1@20@@oe@16-12-2010 1009033805@GENIA Treebank@formal@@1@S@SERCA activity was measured as the thapsigargin sensitive, Ca2+ dependent and ouabain resistant, ATP hydrolyses in platelet membranes.@@@@1@21@@oe@16-12-2010 1009033806@GENIA Treebank@formal@@1@S@Relative expressions of SERCA 2 and 3 isoforms and Ras-related protein (Rap) 1 in platelet membranes were determined by Western immunoblots.@@@@1@24@@oe@16-12-2010 1009033807@GENIA Treebank@formal@@1@S@Highly significant correlations were observed for FECa2+ in the dense tubules with: 1) the maximal reaction velocity (Vmax) of the SERCA (r = 0.592, P = .0014), and 2) Rapl (r = 0.551, P = .0035).@@@@1@49@@oe@16-12-2010 1009033808@GENIA Treebank@formal@@1@S@In addition, negative correlations were observed between FECa2+ in the dense tubules and age.@@@@1@16@@oe@16-12-2010 1009033809@GENIA Treebank@formal@@1@S@No correlations were observed for these variables with blood pressure or serum lipoproteins.@@@@1@14@@oe@16-12-2010 1009033810@GENIA Treebank@formal@@1@S@We conclude the FECa2+ and the Vmax of the SERCA are reliable indicators of Ca2+ load in platelets from women.@@@@1@21@@oe@16-12-2010 1009033811@GENIA Treebank@formal@@1@S@However, in women, unlike previous observations in men, these platelet parameters are not correlated with blood pressure and serum lipoproteins.@@@@1@24@@oe@16-12-2010 1009092301@GENIA Treebank@formal@@1@S@Nonimmunoglobulin gene hypermutation in germinal center B cells.@@@@1@9@@oe@16-12-2010 1009092302@GENIA Treebank@formal@@1@S@Somatic hypermutation is the most critical mechanism underlying the diversification of Ig genes.@@@@1@14@@oe@16-12-2010 1009092303@GENIA Treebank@formal@@1@S@Although mutation occurs specifically in B cells during the germinal center reaction, it remains a matter of debate whether the mutation machinery also targets non-Ig genes.@@@@1@28@@oe@16-12-2010 1009092304@GENIA Treebank@formal@@1@S@We have studied mutations in the 5' noncoding region of the Bcl6 gene in different subtypes of lymphomas.@@@@1@19@@oe@16-12-2010 1009092305@GENIA Treebank@formal@@1@S@We found frequent hypermutation in follicular lymphoma (25 of 59 = 42%) (germinal center cell origin) and mucosa-associated lymphoid tissue (MALT) lymphoma (19 of 45 = 42%) (postgerminal center), but only occasionally in mantle cell lymphoma (1 of 21 = 4.8%) (pregerminal center).@@@@1@62@@oe@16-12-2010 1009092306@GENIA Treebank@formal@@1@S@Most mutations were outside the motifs potentially important for transcription, suggesting they were not important in lymphomagenesis but may, like Ig mutation, represent an inherent feature of the lymphoma precursor cells.@@@@1@35@@oe@16-12-2010 1009092307@GENIA Treebank@formal@@1@S@Therefore, we investigated their normal cell counterparts microdissected from a reactive tonsil.@@@@1@14@@oe@16-12-2010 1009092308@GENIA Treebank@formal@@1@S@Bcl6 mutation was found in 13 of 24 (54%) clones from the germinal centre but only in 1 of 24 (4%) clones from the naive B cells of the mantle zone.@@@@1@38@@oe@16-12-2010 1009092309@GENIA Treebank@formal@@1@S@The frequency, distribution, and nature of these mutations were similar to those resulting from the Ig hypermutation process.@@@@1@21@@oe@16-12-2010 1009092310@GENIA Treebank@formal@@1@S@The results show unequivocal evidence of non-Ig gene hypermutation in germinal center B cells and provide fresh insights into the process of hypermutation and lymphomagenesis.@@@@1@26@@oe@16-12-2010 1009093101@GENIA Treebank@formal@@1@S@1,25-Dihydroxyvitamin D3 induces differentiation of a retinoic acid-resistant acute promyelocytic leukemia cell line (UF-1) associated with expression of p21(WAF1/CIP1) and p27(KIP1).@@@@1@24@@oe@16-12-2010 1009093102@GENIA Treebank@formal@@1@S@Retinoic acid (RA) resistance is a serious problem for patients with acute promyelocytic leukemia (APL) who are receiving all-trans RA.@@@@1@25@@oe@16-12-2010 1009093103@GENIA Treebank@formal@@1@S@However, the mechanisms and strategies to overcome RA resistance by APL cells are still unclear.@@@@1@17@@oe@16-12-2010 1009093104@GENIA Treebank@formal@@1@S@The biologic effects of RA are mediated by two distinct families of transcriptional factors: RA receptors (RARs) and retinoid X receptors (RXRs).@@@@1@28@@oe@16-12-2010 1009093105@GENIA Treebank@formal@@1@S@RXRs heterodimerize with 1, 25-dihydroxyvitamin D3 [1,25(OH)2D3] receptor (VDR), enabling their efficient transcriptional activation.@@@@1@19@@oe@16-12-2010 1009093106@GENIA Treebank@formal@@1@S@The cyclin-dependent kinase (cdk) inhibitor p21(WAF1/CIP1) has a vitamin D3-responsive element (VDRE) in its promoter, and 1,25(OH)2D3 enhances the expression of p21(WAF1/CIP1) and induces differentiation of selected myeloid leukemic cell lines.@@@@1@37@@oe@16-12-2010 1009093107@GENIA Treebank@formal@@1@S@We have recently established a novel APL cell line (UF-1) with features of RA resistance.@@@@1@18@@oe@16-12-2010 1009093108@GENIA Treebank@formal@@1@S@1,25(OH)2D3 can induce growth inhibition and G1 arrest of UF-1 cells, resulting in differentiation of these cells toward granulocytes.@@@@1@21@@oe@16-12-2010 1009093109@GENIA Treebank@formal@@1@S@This 1, 25(OH)2D3-induced G1 arrest is enhanced by all-trans RA.@@@@1@10@@oe@16-12-2010 1009093110@GENIA Treebank@formal@@1@S@Also, 1, 25(OH)2D3 (10(-10) to 10(-7) mol/L) in combination with RA markedly inhibits cellular proliferation in a dose- and time-dependent manner.@@@@1@24@@oe@16-12-2010 1009093111@GENIA Treebank@formal@@1@S@Associated with these findings, the levels of p21(WAF1/CIP1) and p27(KIP1) mRNA and protein increased in these cells.@@@@1@19@@oe@16-12-2010 1009093112@GENIA Treebank@formal@@1@S@Northern blot analysis showed that p21(WAF1/CIP1) and p27(KIP1) mRNA and protein increased in these cells.@@@@1@16@@oe@16-12-2010 1009093113@GENIA Treebank@formal@@1@S@Northern blot analysis showed that p21(WAF1/CIP1) and p27(KIP1) transcripts were induced after 6 hours' exposure to 1,25(OH)2D3 and then decreased to basal levels over 48 hours.@@@@1@28@@oe@16-12-2010 1009093114@GENIA Treebank@formal@@1@S@Western blot experiments showed that p21(WAF1/CIP1) protein levels increased and became detectable after 12 hours of 1,25(OH)2D3 treatment and induction of p27(KIP1) protein was much more gradual and sustained in UF-1 cells.@@@@1@33@@oe@16-12-2010 1009093115@GENIA Treebank@formal@@1@S@Interestingly, the combination of 1, 25(OH)2D3 and RA markedly enhanced the levels of p27(KIP1) transcript and protein as compared with levels induced by 1, 25(OH)2D3 alone.@@@@1@26@@oe@16-12-2010 1009093116@GENIA Treebank@formal@@1@S@In addition, exogenous p27(KIP1) expression can enhance the level of CD11b antigen in myeloid leukemic cells.@@@@1@18@@oe@16-12-2010 1009093117@GENIA Treebank@formal@@1@S@In contrast, RA alone can induce G1 arrest of UF-1 cells; however, it did not result in an increase of p21(WAF1/CIP1) and p27(KIP1) transcript and protein expression in RA-resistant cells.@@@@1@34@@oe@16-12-2010 1009093118@GENIA Treebank@formal@@1@S@Taken together, we conclude that 1,25(OH)2D3 induces increased expression of cdk inhibitors, which mediates a G1 arrest, and this may be associated with differentiation of RA-resistant UF-1 cells toward mature granulocytes.@@@@1@35@@oe@16-12-2010 1009094201@GENIA Treebank@formal@@1@S@Human immunodeficiency virus-associated Hodgkin's disease derives from post-germinal center B cells.@@@@1@13@@oe@16-12-2010 1009094202@GENIA Treebank@formal@@1@S@Human immunodeficiency virus-associated Hodgkin's disease (HIV-HD) displays several peculiarities when compared with HD of the general population.@@@@1@21@@oe@16-12-2010 1009094203@GENIA Treebank@formal@@1@S@These include overrepresentation of clinically aggressive histologic types and frequent infection of Reed-Sternberg (RS) cells by Epstein-Barr virus (EBV).@@@@1@24@@oe@16-12-2010 1009094204@GENIA Treebank@formal@@1@S@Recently, we have reported that the histogenesis of HD of the general population may be assessed by monitoring the expression pattern of BCL-6, a transcription factor expressed in germinal center (GC) B cells, and of CD138/syndecan-1 (syn-1), a proteoglycan associated with post-GC, terminal B-cell differentiation.@@@@1@55@@oe@16-12-2010 1009094205@GENIA Treebank@formal@@1@S@In this study, we have applied these two markers to the study of HIV-HD histogenesis and correlated their expression status to the virologic features of this disease.@@@@1@29@@oe@16-12-2010 1009094206@GENIA Treebank@formal@@1@S@We have found that RS cells of all histologic categories of HIV-HD consistently display the BCL-6(-)/syn-1(+) phenotype and thus reflect post-GC B cells.@@@@1@24@@oe@16-12-2010 1009094207@GENIA Treebank@formal@@1@S@Although BCL-6(-)/syn-1(+)RS cells of HIV-HD express CD40, they are not surrounded by CD40 ligand-positive (CD40L+) reactive T lymphocytes, which, in HD of the general population, are thought to regulate the disease phenotype through CD40/CD40L interactions.@@@@1@43@@oe@16-12-2010 1009094208@GENIA Treebank@formal@@1@S@Conversely, RS cells of virtually all HIV-HD express the EBV-encoded latent membrane protein 1 (LMP1), which, being functionally homologous to CD40, may contribute, at least in part, to the modulation of the HIV-HD phenotype.@@@@1@43@@oe@16-12-2010 1009094701@GENIA Treebank@formal@@1@S@Constitutive activation of NF-kappaB in primary adult T-cell leukemia cells.@@@@1@11@@oe@16-12-2010 1009094702@GENIA Treebank@formal@@1@S@Human T-cell leukemia virus type I (HTLV-I) is an etiologic agent of adult T-cell leukemia (ATL).@@@@1@21@@oe@16-12-2010 1009094703@GENIA Treebank@formal@@1@S@The viral protein Tax induces the activation and nuclear translocalization of transcription factor NF-kappaB, which is proposed to play a crucial role in the transformation of T cells by HTLV-I.@@@@1@32@@oe@16-12-2010 1009094704@GENIA Treebank@formal@@1@S@However, the HTLV-I genes including Tax are not expressed significantly in primary leukemic cells from ATL patients.@@@@1@19@@oe@16-12-2010 1009094705@GENIA Treebank@formal@@1@S@In this study, we examined the basis for NF-kappaB activation in freshly isolated leukemic cells from ATL patients.@@@@1@20@@oe@16-12-2010 1009094706@GENIA Treebank@formal@@1@S@We found that leukemic cells from ATL patients, like HTLV-I-infected T-cell lines, display constitutive NF-kappaB DNA binding activity and increased degradation of IkappaBalpha (an inhibitor of NF-kappaB).@@@@1@32@@oe@16-12-2010 1009094707@GENIA Treebank@formal@@1@S@Whereas the NF-kappaB binding activity in Tax-expressing T-cell lines consisted mostly of p50/c-Rel, fresh ATL samples contained p50/p50 and p50/p65 heterodimers.@@@@1@23@@oe@16-12-2010 1009094708@GENIA Treebank@formal@@1@S@One T-cell line derived from ATL leukemic cells, TL-Om1, displayed constitutive NF-kappaB activity, as well as enhanced degradation of IkappaBalpha, despite the lack of detectable Tax expression.@@@@1@32@@oe@16-12-2010 1009094709@GENIA Treebank@formal@@1@S@Interestingly, the NF-kappaB in TL-Om1 consists of p50/p50 and p50/p65 like that in fresh primary leukemic cells.@@@@1@19@@oe@16-12-2010 1009094710@GENIA Treebank@formal@@1@S@Our results suggest that activation of NF-kappaB occurs through a Tax-independent mechanism in leukemic cells of ATL patients, possibly due to differential NF-kappaB subunit activation.@@@@1@27@@oe@16-12-2010 1009207601@GENIA Treebank@formal@@1@S@Apoptosis-resistant T cells have a deficiency in NF-kappaB-mediated induction of Fas ligand transcription.@@@@1@14@@oe@16-12-2010 1009207602@GENIA Treebank@formal@@1@S@Apoptosis induced through the TCR in CD4+ T cells is mostly mediated by the inducible expression of Fas ligand (FasL) as a primary event leading to the commitment to death.@@@@1@33@@oe@16-12-2010 1009207603@GENIA Treebank@formal@@1@S@To gain a better understanding of the transcriptional events that regulate this expression, we took advantage of our previously described mutant Jurkat cells.@@@@1@25@@oe@16-12-2010 1009207604@GENIA Treebank@formal@@1@S@These cells are deficient in FasL expression and apoptosis induced upon TCR triggering, although their cytokine (IL-2 and IFN-gamma) production is normal.@@@@1@26@@oe@16-12-2010 1009207605@GENIA Treebank@formal@@1@S@Here we show that both a FasL- and a consensus NF-kappaB- reporter construct are inefficiently induced in these cells compared to wild-type cells.@@@@1@23@@oe@16-12-2010 1009207606@GENIA Treebank@formal@@1@S@In addition, we demonstrate that the inducible transcriptional activity of the FasL reporter is abolished by specific inhibitors of NF-kappaB activation.@@@@1@23@@oe@16-12-2010 1009207607@GENIA Treebank@formal@@1@S@Thus, we could trace the deficit of the mutant cells to an inefficient NF-kappaB activation, evidencing a relevant role for NF-kappaB in the regulation of FasL expression in activated T cells.@@@@1@34@@oe@16-12-2010 1009207608@GENIA Treebank@formal@@1@S@Furthermore, our results suggest that the induction of FasL versus cytokine gene expression is differentially sensitive to NF-kappaB deprivation.@@@@1@21@@oe@16-12-2010 1009209101@GENIA Treebank@formal@@1@S@NF-kappaB regulates Fas/APO-1/CD95- and TCR- mediated apoptosis of T lymphocytes.@@@@1@10@@oe@16-12-2010 1009209102@GENIA Treebank@formal@@1@S@The maintenance of lymphocyte homeostasis by apoptosis is a critical regulatory mechanism in the normal immune system.@@@@1@18@@oe@16-12-2010 1009209103@GENIA Treebank@formal@@1@S@The transcription factor NF-kappaB has been shown to play a role in protecting cells against death mediated by TNF@@@@1@19@@oe@16-12-2010 1009209104@GENIA Treebank@formal@@1@S@We show here that NF-kappaB also has a role in regulating Fas/APO-1/CD95-mediated death, a major pathway of peripheral T cell death.@@@@1@23@@oe@16-12-2010 1009209105@GENIA Treebank@formal@@1@S@Transfection of Jurkat cells with the NF-kappaB subunits p50 and p65 confers resistance against Fas-mediated apoptosis.@@@@1@17@@oe@16-12-2010 1009209106@GENIA Treebank@formal@@1@S@Reciprocally, inhibition of NF-kappaB activation by a soluble peptide inhibitor or a dominant form of the NF-kappaB inhibitor, IkappaB, makes the cells more susceptible to Fas-mediated apoptosis.@@@@1@31@@oe@16-12-2010 1009209107@GENIA Treebank@formal@@1@S@Furthermore, inhibition of NF-kappaB activation by a soluble peptide inhibitor rendered a T cell hybridoma more susceptible to TCR-mediated apoptosis.@@@@1@22@@oe@16-12-2010 1009209108@GENIA Treebank@formal@@1@S@Correspondingly, transfection of p50 and p65 provided considerable protection from TCR-mediated apoptosis.@@@@1@14@@oe@16-12-2010 1009209109@GENIA Treebank@formal@@1@S@These observations were corroborated by studies on Fas-mediated death in primary T cells.@@@@1@14@@oe@16-12-2010 1009209110@GENIA Treebank@formal@@1@S@Concanavalin A-activated cycling T cell blasts from mice that are transgenic for the dominant IkappaB molecule have increased sensitivity to Fas-mediated apoptosis, associated with a down-regulation of NF-kappaB complexes in the nucleus.@@@@1@34@@oe@16-12-2010 1009209111@GENIA Treebank@formal@@1@S@In addition, blocking TNF, itself a positive regulator of NF-kappaB, with neutralizing antibodies renders the cells more susceptible to anti-Fas-mediated apoptosis.@@@@1@25@@oe@16-12-2010 1009209112@GENIA Treebank@formal@@1@S@In summary, our results provide compelling evidence that NF-kappaB protects against Fas-mediated death and is likely to be an important regulator of T cell homeostasis and tolerance.@@@@1@29@@oe@16-12-2010 1009210901@GENIA Treebank@formal@@1@S@Interferon-beta mediates stromal cell rescue of T cells from apoptosis.@@@@1@11@@oe@16-12-2010 1009210902@GENIA Treebank@formal@@1@S@The resolution of immune responses is characterized by extensive apoptosis of activated T cells.@@@@1@15@@oe@16-12-2010 1009210903@GENIA Treebank@formal@@1@S@However, to generate and maintain immunological memory, some antigen-specific T cells must survive and revert to a resting G0/G1 state.@@@@1@23@@oe@16-12-2010 1009210904@GENIA Treebank@formal@@1@S@Cytokines that bind to the common gamma chain of the IL-2 receptor promote the survival of T cell blasts, but also induce proliferation.@@@@1@25@@oe@16-12-2010 1009210905@GENIA Treebank@formal@@1@S@In contrast, soluble factors secreted by stromal cells induce Tcell survival in a resting G0/G1 state.@@@@1@19@@oe@16-12-2010 1009210906@GENIA Treebank@formal@@1@S@We now report that interferon-beta is the principal mediator of stromal cell-mediated Tcell rescue from apoptosis.@@@@1@18@@oe@16-12-2010 1009210907@GENIA Treebank@formal@@1@S@Interferon-alpha and -beta promote the reversion of blast Tcells to a resting G0/G1 configuration with all the characteristic features of stromal cell rescue; such as high Bcl-XL expression and low Bcl-2.@@@@1@34@@oe@16-12-2010 1009210908@GENIA Treebank@formal@@1@S@Type I interferons and stromal cells stimulate apparently identical signaling pathways, leading to STAT-1 activation.@@@@1@17@@oe@16-12-2010 1009210909@GENIA Treebank@formal@@1@S@We also show that this mechanism may play a fundamental role in the persistence of T cells at sites of chronic inflammation; suggesting that chronic inflammation is an aberrant consequence of immunological memory.@@@@1@35@@oe@16-12-2010 1009277501@GENIA Treebank@formal@@1@S@Evidence for distinct intracellular signaling pathways in CD34+ progenitor to dendritic cell differentiation from a human cell line model.@@@@1@20@@oe@16-12-2010 1009277502@GENIA Treebank@formal@@1@S@Intracellular signals that mediate differentiation of pluripotent hemopoietic progenitors to dendritic cells (DC) are largely undefined.@@@@1@19@@oe@16-12-2010 1009277503@GENIA Treebank@formal@@1@S@We have previously shown that protein kinase C (PKC) activation (with phorbol ester (PMA) alone) specifically induces differentiation of primary human CD34+ hemopoietic progenitor cells (HPC) to mature DC.@@@@1@38@@oe@16-12-2010 1009277504@GENIA Treebank@formal@@1@S@We now find that cytokine-driven (granulocyte-macrophage CSF and TNF-alpha) CD34+ HPC-->DC differentiation is preferentially blocked by inhibitors of PKC activation.@@@@1@25@@oe@16-12-2010 1009277505@GENIA Treebank@formal@@1@S@To further identify intracellular signals and downstream events important in CD34+ HPC-->DC differentiation we have characterized a human leukemic cell line model of this process.@@@@1@28@@oe@16-12-2010 1009277506@GENIA Treebank@formal@@1@S@The CD34+ myelomonocytic cell line KG1 differentiates into dendritic-like cells in response to granulocyte-macrophage CSF plus TNF-alpha, or PMA (with or without the calcium ionophore ionomycin, or TNF-alpha), with different stimuli mediating different aspects of the process.@@@@1@43@@oe@16-12-2010 1009277507@GENIA Treebank@formal@@1@S@Phenotypic DC characteristics of KG1 dendritic-like cells include morphology (loosely adherent cells with long neurite processes), MHC I+/MHC IIbright/CD83+/CD86+/CD14- surface Ag expression, and RelB and DC-CK1 gene expression.@@@@1@33@@oe@16-12-2010 1009277508@GENIA Treebank@formal@@1@S@Functional DC characteristics include fluid phase macromolecule uptake (FITC-dextran) and activation of resting T cells.@@@@1@18@@oe@16-12-2010 1009277509@GENIA Treebank@formal@@1@S@Comparison of KG1 to the PMA-unresponsive subline KG1a reveals differences in expression of TNF receptors 1 and 2; PKC isoforms alpha, beta I, beta II, and mu; and RelB, suggesting that these components/pathways are important for DC differentiation.@@@@1@45@@oe@16-12-2010 1009277510@GENIA Treebank@formal@@1@S@Together, these findings demonstrate that cytokine or phorbol ester stimulation of KG1 is a model of human CD34+ HPC to DC differentiation and suggest that specific intracellular signaling pathways mediate specific events in DC lineage commitment.@@@@1@38@@oe@16-12-2010 1009278301@GENIA Treebank@formal@@1@S@IL-2-mediated cell cycle progression and inhibition of apoptosis does not require NF-kappa B or activating protein-1 activation in primary human T cells.@@@@1@23@@oe@16-12-2010 1009278302@GENIA Treebank@formal@@1@S@The IL-2 growth hormone is the major growth factor of activated T lymphocytes during a developing immune response.@@@@1@19@@oe@16-12-2010 1009278303@GENIA Treebank@formal@@1@S@IL-2 is required not only for cell cycle progression but also to protect Ag-activated T cells from programmed cell death.@@@@1@21@@oe@16-12-2010 1009278304@GENIA Treebank@formal@@1@S@In several cell types, activation of NF-kappa B and/or activating protein-1 (AP-1) has been demonstrated to be extremely important in blocking apoptosis.@@@@1@26@@oe@16-12-2010 1009278305@GENIA Treebank@formal@@1@S@To determine whether either or both of these transcription factors are involved in cell survival or cell cycle progression in response to IL-2, primary human T cells responsive to the growth factor were analyzed for NF-kappa B and AP-1 activation.@@@@1@42@@oe@16-12-2010 1009278306@GENIA Treebank@formal@@1@S@The current study clearly demonstrates that IL-2 does not induce I kappa B alpha degradation or NF-kappa B activation in primary human T cells that respond to IL-2 by entering the cell cycle and avoiding apoptosis.@@@@1@37@@oe@16-12-2010 1009278307@GENIA Treebank@formal@@1@S@Similarly, IL-2 neither activates JNK nor increases AP-1 binding activity to a consensus o-tetradecanoylphorbol 13-acetate (TPA) response element.@@@@1@22@@oe@16-12-2010 1009278308@GENIA Treebank@formal@@1@S@On the other hand, the growth factor does induce the activation of STAT3 and STAT5 in these cells, as has been previously demonstrated.@@@@1@26@@oe@16-12-2010 1009278309@GENIA Treebank@formal@@1@S@These data show that neither NF-kappa B nor AP-1 activation is required for IL-2-mediated survival or cell cycle progression in activated primary human T cells.@@@@1@26@@oe@16-12-2010 1009280101@GENIA Treebank@formal@@1@S@Impaired fetal thymocyte development after efficient adenovirus-mediated inhibition of NF-kappa B activation.@@@@1@13@@oe@16-12-2010 1009280102@GENIA Treebank@formal@@1@S@We introduce a new experimental system combining adenovirus-mediated gene transfer and fetal thymic organ culture (FTOC).@@@@1@19@@oe@16-12-2010 1009280103@GENIA Treebank@formal@@1@S@This system allowed us to efficiently express in developing thymocytes a mutant form of the NF-kappa B inhibitor I kappa B alpha (mut-I kappa B) and to study the maturation defects occurring when NF-kappa B activation is inhibited during fetal development.@@@@1@44@@oe@16-12-2010 1009280104@GENIA Treebank@formal@@1@S@Fetal thymocytes infected with adenovirus containing mut-I kappa B were found to develop normally until the CD44-CD25+, CD4-CD8- double-negative stage, while production of more mature double-positive and single-positive populations was strongly decreased.@@@@1@35@@oe@16-12-2010 1009280105@GENIA Treebank@formal@@1@S@Proliferation, as measured by the percentage of cells in cycle appeared normal, as did rearrangement and expression of the TCR beta-chain.@@@@1@24@@oe@16-12-2010 1009280106@GENIA Treebank@formal@@1@S@However, apoptosis was much higher in FTOC infected with adenovirus containing mut-I kappa B than in FTOC infected with a control virus.@@@@1@24@@oe@16-12-2010 1009280107@GENIA Treebank@formal@@1@S@Taken together, these results suggest that NF-kappa B plays a crucial role in ensuring the differentiation and survival of thymocytes in the early stages of their development.@@@@1@29@@oe@16-12-2010 1009280501@GENIA Treebank@formal@@1@S@Differential regulation of 4E-BP1 and 4E-BP2, two repressors of translation initiation, during human myeloid cell differentiation.@@@@1@19@@oe@16-12-2010 1009280502@GENIA Treebank@formal@@1@S@Human myeloid differentiation is accompanied by a decrease in cell proliferation.@@@@1@12@@oe@16-12-2010 1009280503@GENIA Treebank@formal@@1@S@Because the translation rate is an important determinant of cell proliferation, we have investigated translation initiation during human myeloid cell differentiation using the HL-60 promyelocytic leukemia cell line and the U-937 monoblastic cell line.@@@@1@36@@oe@16-12-2010 1009280504@GENIA Treebank@formal@@1@S@A decrease in the translation rate is observed when the cells are induced to differentiate along the monocytic/macrophage pathway or along the granulocytic pathway.@@@@1@25@@oe@16-12-2010 1009280505@GENIA Treebank@formal@@1@S@The inhibition in protein synthesis correlates with specific regulation of two repressors of translation initiation, 4E-BP1 and 4E-BP2.@@@@1@20@@oe@16-12-2010 1009280506@GENIA Treebank@formal@@1@S@Induction of HL-60 and U-937 cell differentiation into monocytes/macrophages by IFN-gamma or PMA results in a dephosphorylation and consequent activation of 4E-BP1.@@@@1@23@@oe@16-12-2010 1009280507@GENIA Treebank@formal@@1@S@Dephosphorylation of 4E-BP1 was also observed when U-937 cells were induced to differentiate into monocytes/macrophages following treatment with retinoic acid or DMSO.@@@@1@23@@oe@16-12-2010 1009280508@GENIA Treebank@formal@@1@S@In contrast, treatment of HL-60 cells with retinoic acid or DMSO, which results in a granulocytic differentiation of these cells, decreases 4E-BP1 amount without affecting its phosphorylation and strongly increases 4E-BP2 amount.@@@@1@36@@oe@16-12-2010 1009280509@GENIA Treebank@formal@@1@S@Taken together, these data provide evidence for differential regulation of the translational machinery during human myeloid differentiation, specific to the monocytic/macrophage pathway or to the granulocytic pathway.@@@@1@30@@oe@16-12-2010 1009282501@GENIA Treebank@formal@@1@S@Glucocorticoids promote nonphlogistic phagocytosis of apoptotic leukocytes.@@@@1@8@@oe@16-12-2010 1009282502@GENIA Treebank@formal@@1@S@Phagocyte recognition, uptake, and nonphlogistic degradation of neutrophils and other leukocytes undergoing apoptosis promote the resolution of inflammation.@@@@1@21@@oe@16-12-2010 1009282503@GENIA Treebank@formal@@1@S@This study assessed the effects of anti-inflammatory glucocorticoids on this leukocyte clearance mechanism.@@@@1@14@@oe@16-12-2010 1009282504@GENIA Treebank@formal@@1@S@Pretreatment of "semimature" 5-day human monocyte-derived macrophages (M phi) for 24 h with methylprednisolone, dexamethasone, and hydrocortisone, but not the nonglucocorticoid steroids aldosterone, estradiol, and progesterone, potentiated phagocytosis of apoptotic neutrophils.@@@@1@42@@oe@16-12-2010 1009282505@GENIA Treebank@formal@@1@S@These effects were specific in that the potentiated phagocytosis of apoptotic neutrophils was completely blocked by the glucocorticoid receptor antagonist RU38486, and glucocorticoids did not promote 5-day M phi ingestion of opsonized erythrocytes.@@@@1@35@@oe@16-12-2010 1009282506@GENIA Treebank@formal@@1@S@Similar glucocorticoid-mediated potentiation was observed with 5-day M phi uptake of alternative apoptotic "targets" (eosinophils and Jurkat T cells) and in uptake of apoptotic neutrophils by alternative phagocytes (human glomerular mesangial cells and murine M phi elicited into the peritoneum or derived from bone marrow).@@@@1@52@@oe@16-12-2010 1009282507@GENIA Treebank@formal@@1@S@Importantly, methylprednisolone-mediated enhancement of the uptake of apoptotic neutrophils did not trigger the release of the chemokines IL-8 and monocyte chemoattractant protein-1.@@@@1@24@@oe@16-12-2010 1009282508@GENIA Treebank@formal@@1@S@Furthermore, longer-term potentiation by methylprednisolone was observed in maturing human monocyte-derived M phi, with greater increases in 5-day M phi uptake of apoptotic cells being observed the earlier glucocorticoids were added during monocyte maturation into M phi.@@@@1@40@@oe@16-12-2010 1009282509@GENIA Treebank@formal@@1@S@We conclude that potentiation of nonphlogistic clearance of apoptotic leukocytes by phagocytes is a hitherto unrecognized property of glucocorticoids that has potential implications for therapies aimed at promoting the resolution of inflammatory diseases.@@@@1@34@@oe@16-12-2010 1009656101@GENIA Treebank@formal@@1@S@Stimulation of CD40 on immunogenic human malignant melanomas augments their cytotoxic T lymphocyte-mediated lysis and induces apoptosis.@@@@1@18@@oe@16-12-2010 1009656102@GENIA Treebank@formal@@1@S@Here, we report the functional expression of CD40 on human malignant melanomas (MMs).@@@@1@17@@oe@16-12-2010 1009656103@GENIA Treebank@formal@@1@S@Comparison of tumor specimen from MM precursor lesions, primary tumors, and metastases revealed that CD40 surface expression is down-regulated during tumor progression.@@@@1@25@@oe@16-12-2010 1009656104@GENIA Treebank@formal@@1@S@CD40 expression was confirmed in 7 human MM cell lines established from immunogenic primary tumors or metastases, whereas 11 cell lines established from advanced stages were CD40 negative.@@@@1@30@@oe@16-12-2010 1009656105@GENIA Treebank@formal@@1@S@CD40 expression could be enhanced in CD40-positive MM by stimulation with IFN-gamma and tumor necrosis factor-alpha but not by interleukin (IL)-1beta or CD40 triggering.@@@@1@28@@oe@16-12-2010 1009656106@GENIA Treebank@formal@@1@S@CD40 ligation on MM by CD40L-transfected murine L-cells or by a soluble CD40L fusion protein up-regulated their expression of intercellular adhesion molecule-1 and MHC class I and class II molecules and their secretion of IL-6, IL-8, tumor necrosis factor-a, and granulocyte macrophage colony-stimulating factor and also induced a rapid activation of the transcription factor nuclear factor kappaB.@@@@1@61@@oe@16-12-2010 1009656107@GENIA Treebank@formal@@1@S@Furthermore, CD40 ligation of a HLA-A2+, MelanA/MART1+ MM cell line enhanced its susceptibility to specific lysis by a HLA-A2-restricted, MelanA/MART-1-specific CTL clone.@@@@1@26@@oe@16-12-2010 1009656108@GENIA Treebank@formal@@1@S@Finally, CD40 ligation induced growth inhibition and apoptosis in MM.@@@@1@12@@oe@16-12-2010 1009656109@GENIA Treebank@formal@@1@S@These results indicate that CD40-CD40L interactions may play an important role in augmenting antitumor immunity and inducing apoptosis in some CD40-positive immunogenic human MMs.@@@@1@25@@oe@16-12-2010 1009657401@GENIA Treebank@formal@@1@S@Glucocorticoid-induced cell death requires autoinduction of glucocorticoid receptor expression in human leukemic T cells.@@@@1@15@@oe@16-12-2010 1009657402@GENIA Treebank@formal@@1@S@In contrast to the negative autoregulation of glucocorticoid receptor (GR) expression seen in most cells and tissues, GR expression is positively autoregulated in human leukemic T cells and in other cells sensitive to glucocorticoid-induced cell death.@@@@1@40@@oe@16-12-2010 1009657403@GENIA Treebank@formal@@1@S@To determine whether positive autoregulation is a necessary component of glucocorticoid-induced cell death, a wild-type GR gene under the control of a tetracycline-regulated promoter was stably transfected into glucocorticoid-resistant cells lacking endogenous functional receptor.@@@@1@36@@oe@16-12-2010 1009657404@GENIA Treebank@formal@@1@S@Transfectants grown in the presence of tetracycline contained about 15,000 receptors/cell, a value approximately equal to basal level GR expression in glucocorticoid-sensitive 6TG1.1 cells before steroid treatment.@@@@1@29@@oe@16-12-2010 1009657405@GENIA Treebank@formal@@1@S@Under these conditions, dexamethasone had a minimal effect on cell growth, elicited little internucleosomal DNA fragmentation, and induced no cell cycle perturbation.@@@@1@26@@oe@16-12-2010 1009657406@GENIA Treebank@formal@@1@S@In the absence of tetracycline, GR mRNA and protein expression increased 2-3-fold, and cells expressed 48,000 receptors, a level nearly equivalent to that present in 6TG1.1 cells after 18 h of autoinduction.@@@@1@36@@oe@16-12-2010 1009657407@GENIA Treebank@formal@@1@S@Under these conditions, dexamethasone markedly inhibited cell growth, caused G1 arrest, and induced significant internucleosomal DNA fragmentation.@@@@1@21@@oe@16-12-2010 1009657408@GENIA Treebank@formal@@1@S@These studies therefore suggest that basal level GR expression is inadequate to mediate glucocorticoid-induced apoptosis in glucocorticoid-sensitive T cells and that positive autoregulation is a necessary component of this process.@@@@1@31@@oe@16-12-2010 1009778801@GENIA Treebank@formal@@1@S@Jeg-3 human choriocarcinoma-induced immunosuppression: downregulation of interleukin-2, interleukin-2 receptor alpha-chain, and its Jak/Stat signaling pathway.@@@@1@19@@oe@16-12-2010 1009778802@GENIA Treebank@formal@@1@S@PROBLEM: The mechanisms of the immunosuppressive and immunosuppression-inducing capacities of Jeg-3 human choriocarcinoma cell line supernatants (HCSs) are not yet completely understood.@@@@1@26@@oe@16-12-2010 1009778803@GENIA Treebank@formal@@1@S@The influence on interleukin (IL)-2, IL-4 and interferon (IFN)-gamma production; IL-2 receptor (IL-2R) alpha-, beta-, and gamma-chain; and the signaling pathway molecules Janus kinase (Jak)1, Jak3, signal transducers and activators of transcription (Stat)1, Stat3, and Stat5 should be investigated.@@@@1@63@@oe@16-12-2010 1009778804@GENIA Treebank@formal@@1@S@METHOD OF STUDY: For assessment of IL production, whole peripheral venous blood from healthy donors was stimulated with phorbol-myristate-acetate and ionomycine.@@@@1@24@@oe@16-12-2010 1009778805@GENIA Treebank@formal@@1@S@Secretion of ILs was blocked with monensine.@@@@1@8@@oe@16-12-2010 1009778806@GENIA Treebank@formal@@1@S@Intracellular ILs were analyzed by flow cytometry.@@@@1@8@@oe@16-12-2010 1009778807@GENIA Treebank@formal@@1@S@For IL-2R and signaling pathway molecule analysis, peripheral blood lymphocytes were stimulated with phytohemagglutinin (PHA).@@@@1@19@@oe@16-12-2010 1009778808@GENIA Treebank@formal@@1@S@IL-2R chains were measured by flow cytometry, and Jaks/Stats by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot.@@@@1@24@@oe@16-12-2010 1009778809@GENIA Treebank@formal@@1@S@RESULTS: Phorbol-myristate-acetate and ionomycine strongly increase the percent-age of IL-2+ cells; an additional 50% HCSs significantly suppresses the percentage to, or below the level of unstimulated cells.@@@@1@32@@oe@16-12-2010 1009778810@GENIA Treebank@formal@@1@S@IFN-gamma production is strongly decreased by HCSs in some cases, but not in others.@@@@1@16@@oe@16-12-2010 1009778811@GENIA Treebank@formal@@1@S@PHA stimulates IL-2R alpha-, beta-, and gamma-chain expression and their signaling pathway molecules Jak1, Jak3, Stat1, Stat3, and Stat5.@@@@1@26@@oe@16-12-2010 1009778812@GENIA Treebank@formal@@1@S@50% HCS downregulates the alpha-chain and slightly upregulates the beta-chain.@@@@1@12@@oe@16-12-2010 1009778813@GENIA Treebank@formal@@1@S@Jak1, Jak3, Stat1, Stat3, and Stat5 expression is suppressed approximately to, or below the level of unstimulated cells.@@@@1@24@@oe@16-12-2010 1009778814@GENIA Treebank@formal@@1@S@CONCLUSIONS: HCS forcefully blocks the production of IL-2; the IL-2R alpha-chain; and Jak1, Jak3, Stat1, Stat3, and Stat5 expression.@@@@1@27@@oe@16-12-2010 1009778815@GENIA Treebank@formal@@1@S@The observed phenomena might be caused by downregulation of an IL-2R regulation gene, and might play a key role in the expansion of choriocarcinoma, and possibly in the survival of the fetal allograft.@@@@1@36@@oe@16-12-2010 1009860601@GENIA Treebank@formal@@1@S@Characterization of expression of the gene for human pterin carbinolamine dehydratase/dimerization cofactor of HNF1.@@@@1@15@@oe@16-12-2010 1009860602@GENIA Treebank@formal@@1@S@Pterin carbinolamine dehydratase/dimerization cofactor of HNF1 (PCD/DCoH) is a dual-function protein.@@@@1@14@@oe@16-12-2010 1009860603@GENIA Treebank@formal@@1@S@In the cytoplasm it acts as a dehydratase in the regeneration of tetrahydrobiopterin, the cofactor for aromatic amino acid hydroxylases.@@@@1@22@@oe@16-12-2010 1009860604@GENIA Treebank@formal@@1@S@In the nucleus, it functions as a dimerization cofactor of HNF1 and increases the transcriptional activity of HNF1.@@@@1@20@@oe@16-12-2010 1009860605@GENIA Treebank@formal@@1@S@To deepen our understanding of this protein, we characterized its expression in human tissues and cells.@@@@1@18@@oe@16-12-2010 1009860606@GENIA Treebank@formal@@1@S@Human PCD/DCoH was present predominantly in liver and kidney, with significant amounts in testis and ovary, trace amounts in lung, and undetectable levels in whole brain, heart, and spleen.@@@@1@35@@oe@16-12-2010 1009860607@GENIA Treebank@formal@@1@S@It was expressed in all of the cells that were examined.@@@@1@12@@oe@16-12-2010 1009860608@GENIA Treebank@formal@@1@S@Importantly, it was also present in the nucleus of HeLa cells, which lack HNF1, and in the cytoplasm of fibroblasts that have little or no tetrahydrobiopterin.@@@@1@30@@oe@16-12-2010 1009860609@GENIA Treebank@formal@@1@S@The expression of human PCD/DCoH in the liver and nonhepatic cells was compared at both the mRNA and protein levels.@@@@1@21@@oe@16-12-2010 1009860610@GENIA Treebank@formal@@1@S@Although the mRNA level in liver was only fourfold higher than that in keratinocytes and fibroblasts, the hepatic PCD/DCoH protein level was 20-fold higher than that in normal human epidermal keratinocytes and dermal fibroblasts.@@@@1@36@@oe@16-12-2010 1009860611@GENIA Treebank@formal@@1@S@Cloning of the 5' and 3' untranslated region (UTR) of human keratinocyte PCD/DCoH revealed that it has 53 bp more of GC-rich 5' untranslated sequence than the published liver PCD/DCoH.@@@@1@33@@oe@16-12-2010 1009860612@GENIA Treebank@formal@@1@S@In vitro transcription and translation analysis showed that the longer 5' UTR resulted in about a 35% decrease in translation efficiency.@@@@1@23@@oe@16-12-2010 1009860613@GENIA Treebank@formal@@1@S@These data show that human PCD/DCoH is not only present in cells where tetrahydrobiopterin is synthesized or HNF1 is present but is a widely distributed protein.@@@@1@27@@oe@16-12-2010 1009860614@GENIA Treebank@formal@@1@S@Its differential expression in different tissues and cells is regulated not only at the transcriptional level but also at the translational level.@@@@1@23@@oe@16-12-2010 1010100101@GENIA Treebank@formal@@1@S@Essential role of alveolar macrophages in intrapulmonary activation of NF-kappaB.@@@@1@11@@oe@16-12-2010 1010100102@GENIA Treebank@formal@@1@S@Acute inflammatory injury in rat lung induced by deposition of immunoglobulin G immune complexes requires expression of cytokines and chemokines as well as activation of the transcription factor nuclear factor (NF)-kappaB.@@@@1@35@@oe@16-12-2010 1010100103@GENIA Treebank@formal@@1@S@There is little direct evidence regarding the role of alveolar macrophages in these activation events.@@@@1@16@@oe@16-12-2010 1010100104@GENIA Treebank@formal@@1@S@In the present studies, rat lungs were depleted of alveolar macrophages by airway instillation of liposome-encapsulated dichloromethylene diphosphonate.@@@@1@20@@oe@16-12-2010 1010100105@GENIA Treebank@formal@@1@S@These procedures, which greatly reduced the number of retrievable alveolar macrophages, suppressed activation of lung NF-kappaB in the inflammatory model.@@@@1@23@@oe@16-12-2010 1010100106@GENIA Treebank@formal@@1@S@In addition, bronchoalveolar lavage levels of tumor necrosis factor-alpha (TNF-alpha) and the CXC chemokine, macrophage inflammatory protein-2, were substantially reduced.@@@@1@26@@oe@16-12-2010 1010100107@GENIA Treebank@formal@@1@S@In parallel, upregulation of the lung vascular adhesion molecule, intercellular adhesion molecule-1, was greatly reduced by intrapulmonary instillation of phosphonate-containing liposomes.@@@@1@25@@oe@16-12-2010 1010100108@GENIA Treebank@formal@@1@S@Neutrophil accumulation and development of lung injury were also substantially diminished.@@@@1@12@@oe@16-12-2010 1010100109@GENIA Treebank@formal@@1@S@Lung instillation of TNF-alpha in alveolar macrophage-depleted rats restored the NF-kappaB activation response in whole lung.@@@@1@17@@oe@16-12-2010 1010100110@GENIA Treebank@formal@@1@S@These data suggest that, in this inflammatory model, initial activation of NF-kappaB occurs in alveolar macrophages and the ensuing production of TNF-alpha may propagate NF-kappaB activation to other cell types in the lung.@@@@1@36@@oe@16-12-2010 1010103401@GENIA Treebank@formal@@1@S@Inhibition of cyclooxygenase-2 expression by 4-trifluoromethyl derivatives of salicylate, triflusal, and its deacetylated metabolite, 2-hydroxy-4-trifluoromethylbenzoic acid.@@@@1@20@@oe@16-12-2010 1010103402@GENIA Treebank@formal@@1@S@The therapeutic potential of drugs that block the induction of cyclooxygenase-2 has been emphasized.@@@@1@15@@oe@16-12-2010 1010103403@GENIA Treebank@formal@@1@S@When two 4-trifluoromethyl salicylate derivatives [2-acetoxy-4-trifluoromethyl-benzoic acid (triflusal) and its deacetylated metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB)] were compared with aspirin and sodium salicylate as cyclooxygenase-2 (COX-2) inhibitors, we observed that in bacterial lipopolysaccharide-activated human blood, triflusal, aspirin, and HTB, but not sodium salicylate, inhibited COX-2-mediated prostaglandin E2 (PGE2) production (IC50 = 0.16, 0.18, 0.39, and >10 mM, respectively).@@@@1@81@@oe@16-12-2010 1010103404@GENIA Treebank@formal@@1@S@However, only triflusal and aspirin inhibited purified COX-2 enzyme.@@@@1@11@@oe@16-12-2010 1010103405@GENIA Treebank@formal@@1@S@To test this apparent discrepancy, we realized that HTB and triflusal (but neither aspirin nor salicylate) produced a concentration-dependent inhibition of COX-2 protein expression in peripheral human mononuclear cells.@@@@1@33@@oe@16-12-2010 1010103406@GENIA Treebank@formal@@1@S@This observation was further confirmed in a rat air pouch model in vivo, in which both aspirin and triflusal inhibited PGE2 production (ID50 = 18.9 and 11.4 mg/kg p.o., respectively) but only triflusal-treated animals showed a decrease in COX-2 expression.@@@@1@45@@oe@16-12-2010 1010103407@GENIA Treebank@formal@@1@S@This different behavior may be, at least in part, due to the ability of HTB and triflusal to block the activation of the transcription factor nuclear factor-kappaB to a higher extent than aspirin and sodium salicylate.@@@@1@39@@oe@16-12-2010 1010103408@GENIA Treebank@formal@@1@S@Thus, in addition to inhibiting the COX-2 activity at therapeutic concentrations, triflusal is able to block through its metabolite HTB the expression of new enzyme, and hence the resumption of PGE2 synthesis.@@@@1@36@@oe@16-12-2010 1010103409@GENIA Treebank@formal@@1@S@Triflusal and HTB may exert beneficial effects in processes in which de novo COX-2 expression is involved and, in a broader sense, in pathological situations in which genes under nuclear factor-kappaB control are up-regulated.@@@@1@37@@oe@16-12-2010 1010124901@GENIA Treebank@formal@@1@S@Vitamin D receptor 3'-untranslated region polymorphisms: lack of effect on mRNA stability.@@@@1@14@@oe@16-12-2010 1010124902@GENIA Treebank@formal@@1@S@Allelic variation at the 3'-end of the vitamin D receptor (VDR) gene has been associated with a 3-5-fold increased risk of developing prostate cancer and with differences in bone mineralization.@@@@1@33@@oe@16-12-2010 1010124903@GENIA Treebank@formal@@1@S@This genetic diversity does not alter the VDR protein structurally, but instead may be a marker(s) of other, nearby polymorphisms that influence message stability or translation.@@@@1@32@@oe@16-12-2010 1010124904@GENIA Treebank@formal@@1@S@The work reported here was instigated to identify additional VDR 3'-UTR polymorphisms that may have functional significance and to then test whether these genetic variants alter message stability.@@@@1@29@@oe@16-12-2010 1010124905@GENIA Treebank@formal@@1@S@Initially, four novel, frequently occurring sequence variants were identified that associated with two common haplotypes that were described previously.@@@@1@22@@oe@16-12-2010 1010124906@GENIA Treebank@formal@@1@S@These common sequence variants were not found within three message-destabilizing elements that we mapped within the 3'-UTR of the vitamin D receptor mRNA.@@@@1@24@@oe@16-12-2010 1010124907@GENIA Treebank@formal@@1@S@Furthermore, the two VDR 3'-UTR haplotypes conferred an identical half-life on a heterologous beta-globin reporter gene, in an in vitro assay.@@@@1@24@@oe@16-12-2010 1010124908@GENIA Treebank@formal@@1@S@We therefore conclude that common polymorphisms within the VDR 3'-UTR do not influence message stability.@@@@1@16@@oe@16-12-2010 1010160201@GENIA Treebank@formal@@1@S@[Induction of apoptosis in lymphocytes by glucocorticoids: between physiology and pharmacology]@@@@1@14@@oe@16-12-2010 1010160202@GENIA Treebank@formal@@1@S@Glucocorticoids are physiological molecules that are also extensively used in clinics as anti-inflammatory, immunosuppressive or anti-tumoral agents.@@@@1@19@@oe@16-12-2010 1010160203@GENIA Treebank@formal@@1@S@Glucocorticoids can induce apoptosis on normal lymphoid cells and play a key role in the physiology of thymic selection.@@@@1@20@@oe@16-12-2010 1010160204@GENIA Treebank@formal@@1@S@In clinics these molecules are also used for their potencies in inducing apoptosis of malignant lymphoid cells.@@@@1@18@@oe@16-12-2010 1010160205@GENIA Treebank@formal@@1@S@Glucocorticoids are mediating their effects after binding to an intracellular receptor belonging to the steroid receptor superfamily: the glucocorticoid receptor (GR).@@@@1@25@@oe@16-12-2010 1010160206@GENIA Treebank@formal@@1@S@Once activated, the GR, can mediate his effects through direct binding on the DNA or via protein/protein interactions with transcription factors.@@@@1@24@@oe@16-12-2010 1010160207@GENIA Treebank@formal@@1@S@Depending on the type of lymphocytes, the mechanism of apoptosis induced by glucocorticoids fall roughly in two categories: induction of "death genes" by the activated GR (I kappa B, c-jun) or repression of survival factors (AP-1, c-Myc).@@@@1@48@@oe@16-12-2010 1010160208@GENIA Treebank@formal@@1@S@In the case of thymic selection the mechanism is more subtle depending on the mutual repression of Nur77 and GR.@@@@1@21@@oe@16-12-2010 1010262801@GENIA Treebank@formal@@1@S@Expression of IkappaBalpha in the nucleus of human peripheral blood T lymphocytes.@@@@1@13@@oe@16-12-2010 1010262802@GENIA Treebank@formal@@1@S@According to current models the inhibitory capacity of I(kappa)B(alpha) would be mediated through the retention of Rel/NF-kappaB proteins in the cytosol.@@@@1@29@@oe@16-12-2010 1010262803@GENIA Treebank@formal@@1@S@However, I(kappa)B(alpha) has also been detected in the nucleus of cell lines and when overexpressed by transient transfection.@@@@1@27@@oe@16-12-2010 1010262804@GENIA Treebank@formal@@1@S@To gain better insight into the potential role of nuclear I(kappa)B(alpha) in a physiological context we have analysed its presence in the nucleus of human peripheral blood T lymphocytes (PBL).@@@@1@40@@oe@16-12-2010 1010262805@GENIA Treebank@formal@@1@S@We demonstrate the nuclear localization of I(kappa)B(alpha) in PBL by different techniques: Western blot, indirect immunofluorescence and electron microscopy.@@@@1@29@@oe@16-12-2010 1010262806@GENIA Treebank@formal@@1@S@Low levels of nuclear I(kappa)B(alpha) were detected in resting cells whereas a superinduction was obtained after PMA activation.@@@@1@26@@oe@16-12-2010 1010262807@GENIA Treebank@formal@@1@S@The nuclear pool of I(kappa)B(alpha) showed a higher stability than cytosolic I(kappa)B(alpha) and was partially independent of the resynthesis of the protein.@@@@1@37@@oe@16-12-2010 1010262808@GENIA Treebank@formal@@1@S@Unexpectedly, the presence of nuclear I(kappa)B(alpha) did not inhibit NF-kappaB binding to DNA and this phenomenon was not due to the presence of IkappaBbeta at the nuclear level.@@@@1@37@@oe@16-12-2010 1010262809@GENIA Treebank@formal@@1@S@Immunoprecipitation experiments failed to demonstrate an association between nuclear I(kappa)B(alpha) and NF-kappaB proteins.@@@@1@21@@oe@16-12-2010 1010262810@GENIA Treebank@formal@@1@S@Our results demonstrate that in resting and PMA-activated human PBL, I(kappa)B(alpha) is present in the nucleus in an apparently inactive form unable to disrupt NF-kappaB binding from DNA.@@@@1@37@@oe@16-12-2010 1010264101@GENIA Treebank@formal@@1@S@Modulation of the immune response by progesterone-induced lymphocyte factors.@@@@1@10@@oe@16-12-2010 1010264102@GENIA Treebank@formal@@1@S@Rat spleen and peripheral blood lymphocytes express progesterone receptors whose concentration is increased greatly during the early phase of pregnancy.@@@@1@21@@oe@16-12-2010 1010264103@GENIA Treebank@formal@@1@S@After stimulation of progesterone the expression of receptors was augmented 2-3 times.@@@@1@13@@oe@16-12-2010 1010264104@GENIA Treebank@formal@@1@S@When cells were cultured in the presence of progesterone they released a soluble factor that inhibited cellular immunoreactions (MLR, CRC) and cellular proliferation as measured by thymidine incorporation by spleen-cell culture.@@@@1@35@@oe@16-12-2010 1010264105@GENIA Treebank@formal@@1@S@This factor also inhibited the synthesis of anti-DNP antibodies by a mouse hybridoma and diminished the proportion of cells in phase S.@@@@1@23@@oe@16-12-2010 1010264106@GENIA Treebank@formal@@1@S@However, the percentage of asymmetric molecules produced by the hybridoma remained unaltered.@@@@1@14@@oe@16-12-2010 1010264107@GENIA Treebank@formal@@1@S@These results support the hypothesis that soluble factors released by rat lymphocytes modulate the immune response of the mother and participate in the mechanism that protects the fetus against antipaternal antibodies.@@@@1@32@@oe@16-12-2010 1010279101@GENIA Treebank@formal@@1@S@PGG-glucan, a soluble beta-(1,3)-glucan, enhances the oxidative burst response, microbicidal activity, and activates an NF-kappa B-like factor in human PMN: evidence for a glycosphingolipid beta-(1,3)-glucan receptor.@@@@1@32@@oe@16-12-2010 1010279102@GENIA Treebank@formal@@1@S@PGG-Glucan, a soluble beta-(1,6)-branched beta-(1,3)-linked glucose homopolymer derived from the cell wall of the yeast Saccharomyces cerevisiae, is an immunomodulator which enhances leukocyte anti-infective activity and enhances myeloid and megakaryocyte progenitor proliferation.@@@@1@35@@oe@16-12-2010 1010279103@GENIA Treebank@formal@@1@S@Incubation of human whole blood with PGG-Glucan significantly enhanced the oxidative burst response of subsequently isolated blood leukocytes to both soluble and particulate activators in a dose-dependent manner, and increased leukocyte microbicidal activity.@@@@1@35@@oe@16-12-2010 1010279104@GENIA Treebank@formal@@1@S@No evidence for inflammatory cytokine production was obtained under these conditions.@@@@1@12@@oe@16-12-2010 1010279105@GENIA Treebank@formal@@1@S@Electrophoretic mobility shift assays demonstrated that PGG-Glucan induced the activation of an NF-kappaB-like nuclear transcription factor in purified human neutrophils.@@@@1@21@@oe@16-12-2010 1010279106@GENIA Treebank@formal@@1@S@The binding of 3H-PGG-Glucan to human leukocyte membranes was specific, concentration-dependent, saturable, and high affinity (Kd approximately 6 nM).@@@@1@25@@oe@16-12-2010 1010279107@GENIA Treebank@formal@@1@S@A monoclonal antibody specific to the glycosphingolipid lactosylceramide was able to inhibit activation of the NF-kappaB-like factor by PGG-Glucan, and ligand binding data, including polysaccharide specificity, suggested that the PGG-Glucan binding moiety was lactosylceramide.@@@@1@38@@oe@16-12-2010 1010279108@GENIA Treebank@formal@@1@S@These results indicate that PGG-Glucan enhances neutrophil anti-microbial functions and that interaction between this beta-glucan and human neutrophils is mediated by the glycosphingolipid lactosylceramide present at the cell surface.@@@@1@30@@oe@16-12-2010 1010305901@GENIA Treebank@formal@@1@S@Cleavage of transcription factor SP1 by caspases during anti-IgM-induced B-cell apoptosis.@@@@1@12@@oe@16-12-2010 1010305902@GENIA Treebank@formal@@1@S@Apoptosis is instrumental in the processes generating the diversity of the B-cell repertoire.@@@@1@14@@oe@16-12-2010 1010305903@GENIA Treebank@formal@@1@S@Autoreactive B-cells are eliminated by anti-IgM crosslinking after encountering self-antigens, but precise mechanisms leading to B-cell apoptosis are still not well understood.@@@@1@24@@oe@16-12-2010 1010305904@GENIA Treebank@formal@@1@S@We report here the cleavage of the transcription factor SP1 in the human Burkitt lymphoma cell line BL60 during anti-IgM-induced apoptosis.@@@@1@22@@oe@16-12-2010 1010305905@GENIA Treebank@formal@@1@S@Western blot analysis revealed two cleavage products of approximately 68 kDa and 45 kDa after induction of apoptosis.@@@@1@19@@oe@16-12-2010 1010305906@GENIA Treebank@formal@@1@S@Cleavage could be completely inhibited by zDEVD-fmk, an inhibitor specific for caspase 3-like proteases.@@@@1@16@@oe@16-12-2010 1010305907@GENIA Treebank@formal@@1@S@In-vitro cleavage of recombinant SP1 by recombinant caspase 3 (CPP32) or caspase 7 (Mch 3) results in similar cleavage products as those observed in vivo.@@@@1@30@@oe@16-12-2010 1010305908@GENIA Treebank@formal@@1@S@Recombinant caspase 6 (Mch 2) primarily generates a 68-kDa cleavage product, as observed after calcium ionophore (CaI) induced B-cell apoptosis.@@@@1@26@@oe@16-12-2010 1010305909@GENIA Treebank@formal@@1@S@In contrast, caspase 1 (ICE) did not cleave SP1 in vitro.@@@@1@15@@oe@16-12-2010 1010305910@GENIA Treebank@formal@@1@S@The time course of SP1 cleavage during anti-IgM-induced apoptosis is paralleled by an increase of caspase activity measured by DEVD-p-nitroanilide (DEVD-pNA) cleavage.@@@@1@25@@oe@16-12-2010 1010305911@GENIA Treebank@formal@@1@S@DNA band-shift assays revealed a decrease in the intensity of the full length SP1/DNA complex and an increase in the intensity of a smaller complex due to the binding of one SP1 cleavage product.@@@@1@35@@oe@16-12-2010 1010305912@GENIA Treebank@formal@@1@S@By Edman sequencing we could identify a caspase 3 cleavage site after Asp584 (D584AQPQAGR), generating a 22-kDa C-terminal SP1 protein fragment which still contains the DNA binding site.@@@@1@32@@oe@16-12-2010 1010305913@GENIA Treebank@formal@@1@S@Our results show the cleavage of the human transcription factor SP1 in vivo and in vitro, underlining the central role of caspase 3-like proteases during the process of anti-IgM-induced apoptosis.@@@@1@32@@oe@16-12-2010 1018781201@GENIA Treebank@formal@@1@S@Spi-C, a novel Ets protein that is temporally regulated during B lymphocyte development.@@@@1@15@@oe@16-12-2010 1018781202@GENIA Treebank@formal@@1@S@A novel Ets protein was isolated by yeast one-hybrid screening of a cDNA library made from lipopolysaccharide-stimulated mouse splenic B cells, using the SP6 kappa promoter kappaY element as a bait.@@@@1@33@@oe@16-12-2010 1018781203@GENIA Treebank@formal@@1@S@The novel Ets protein was most closely related to PU.1 and Spi-B within the DNA binding Ets domain and was therefore named Spi-C.@@@@1@24@@oe@16-12-2010 1018781204@GENIA Treebank@formal@@1@S@However, Spi-C may represent a novel subgroup within the Ets protein family, as it differed significantly from Spi-B and PU.1 within helix 1 of the Ets domain.@@@@1@30@@oe@16-12-2010 1018781205@GENIA Treebank@formal@@1@S@Spi-C was encoded by a single-copy gene that was mapped to chromosome 10, region C.@@@@1@17@@oe@16-12-2010 1018781206@GENIA Treebank@formal@@1@S@Spi-C interacted with DNA similarly to PU.1 as judged by methylation interference, band-shift and site selection analysis, and activated transcription of a kappaY element reporter gene upon co-transfection of HeLa cells.@@@@1@34@@oe@16-12-2010 1018781207@GENIA Treebank@formal@@1@S@Spi-C RNA was expressed in mature B lymphocytes and at lower levels in macrophages.@@@@1@15@@oe@16-12-2010 1018781208@GENIA Treebank@formal@@1@S@Furthermore, pre-B cell and plasma cell lines were Spi-C-negative, suggesting that Spi-C might be a regulatory molecule during a specific phase of B lymphoid development.@@@@1@28@@oe@16-12-2010 1019193401@GENIA Treebank@formal@@1@S@[Corticoids and allergy]@@@@1@5@@oe@16-12-2010 1019193402@GENIA Treebank@formal@@1@S@Inflammation is constantly observed in allergic reactions.@@@@1@8@@oe@16-12-2010 1019193403@GENIA Treebank@formal@@1@S@Corticosteroids are most effective in preventing the late phase of allergic reaction.@@@@1@13@@oe@16-12-2010 1019193404@GENIA Treebank@formal@@1@S@The action of glucocorticosteroids is mediated through glucocorticoid receptors present in the cellular cytoplasm.@@@@1@15@@oe@16-12-2010 1019193405@GENIA Treebank@formal@@1@S@When activated, glucocorticoid receptors form a dimer and bind to DNA after migration into the nucleus.@@@@1@18@@oe@16-12-2010 1019193406@GENIA Treebank@formal@@1@S@Interaction to DNA induces changes in the transcription rate, leading to either gene induction or gene repression.@@@@1@19@@oe@16-12-2010 1019193407@GENIA Treebank@formal@@1@S@Glucocorticoid receptors are also able to interact with transcriptional factors such as AP-1 (activator protein-1) of NF-kappa B (nuclear factor-kappa B).@@@@1@26@@oe@16-12-2010 1019193408@GENIA Treebank@formal@@1@S@Through these actions glucocorticosteroids are susceptible to modify functions of cells involved in the allergic inflammatory response.@@@@1@18@@oe@16-12-2010 1019193409@GENIA Treebank@formal@@1@S@They are in particular able to inhibit most of the pro-inflammatory functions of the eosinophils.@@@@1@16@@oe@16-12-2010 1019238601@GENIA Treebank@formal@@1@S@A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection [see comments]@@@@1@17@@oe@16-12-2010 1019238602@GENIA Treebank@formal@@1@S@The immunogenetic basis of severe infections caused by bacille Calmette-Guerin vaccine and environmental mycobacteria in humans remains largely unknown.@@@@1@20@@oe@16-12-2010 1019238603@GENIA Treebank@formal@@1@S@We describe 18 patients from several generations of 12 unrelated families who were heterozygous for 1 to 5 overlapping IFNGR1 frameshift small deletions and a wild-type IFNGR1 allele.@@@@1@29@@oe@16-12-2010 1019238604@GENIA Treebank@formal@@1@S@There were 12 independent mutation events at a single mutation site, defining a small deletion hotspot.@@@@1@18@@oe@16-12-2010 1019238605@GENIA Treebank@formal@@1@S@Neighbouring sequence analysis favours a small deletion model of slipped mispairing events during replication.@@@@1@15@@oe@16-12-2010 1019238606@GENIA Treebank@formal@@1@S@The mutant alleles encode cell-surface IFNgamma receptors that lack the intra-cytoplasmic domain, which, through a combination of impaired recycling, abrogated signalling and normal binding to IFNgamma exert a dominant-negative effect.@@@@1@34@@oe@16-12-2010 1019238607@GENIA Treebank@formal@@1@S@We thus report a hotspot for human IFNGR1 small deletions that confer dominant susceptibility to infections caused by poorly virulent mycobacteria.@@@@1@22@@oe@16-12-2010 1019244601@GENIA Treebank@formal@@1@S@Erythroid gene expression is differentially regulated by erythropoietin, haemin and delta-aminolaevulinic acid in UT-7 cells.@@@@1@17@@oe@16-12-2010 1019244602@GENIA Treebank@formal@@1@S@Erythropoietin (Epo) is essential for the later stages of erythropoiesis, acting to promote cell survival and proliferation, but its role in differentiation remains to be defined.@@@@1@31@@oe@16-12-2010 1019244603@GENIA Treebank@formal@@1@S@The UT-7 cell line exhibits both erythroid and megakaryocytic characteristics and can be induced to differentiate along the erythroid pathway by Epo or the megakaryocytic pathway by phorbol myristic acetate.@@@@1@31@@oe@16-12-2010 1019244604@GENIA Treebank@formal@@1@S@We have compared the effects of Epo and the chemical inducers, delta-aminolaevulinic acid (delta-ALA) and haemin on the differentiation capacity of UT-7 cells.@@@@1@27@@oe@16-12-2010 1019244605@GENIA Treebank@formal@@1@S@Epo alone promoted relatively early events in erythroid maturation, without significant changes in haemoglobin production or morphology.@@@@1@19@@oe@16-12-2010 1019244606@GENIA Treebank@formal@@1@S@GATA-2 and c-myb were down-regulated by Epo, and GATA-2 was further down-modulated by the inducers.@@@@1@17@@oe@16-12-2010 1019244607@GENIA Treebank@formal@@1@S@Conversely, SCL expression was up-regulated by Epo and further increased by haemin and delta-ALA.@@@@1@16@@oe@16-12-2010 1019244608@GENIA Treebank@formal@@1@S@Epo caused an increase in the proportion of cells expressing cell surface glycophorin A (GPA) and up-regulated beta- and gamma-globin by several fold.@@@@1@26@@oe@16-12-2010 1019244609@GENIA Treebank@formal@@1@S@Both haemin and delta-ALA caused a de novo increase in alpha-globin expression as well as enhancing Epo-induced beta-globin expression, leading to a marked increase in haemoglobin production.@@@@1@29@@oe@16-12-2010 1019244610@GENIA Treebank@formal@@1@S@These results suggest that haemoglobin production in UT-7 cells is limited by a deficiency of erythroid-specific aminolaevulinic acid synthase (ALAS-E) activity or globin synthesis as a consequence of their immaturity as a multipotential cell line.@@@@1@38@@oe@16-12-2010 1019402001@GENIA Treebank@formal@@1@S@Evidence for a polyclonal etiology of palmar fibromatosis.@@@@1@9@@oe@16-12-2010 1019402002@GENIA Treebank@formal@@1@S@X chromosome inactivation patterns at the androgen receptor locus were evaluated to determine clonality in microdissected lesional tissue and in leukocytes from 2 women with Dupuytren's disease.@@@@1@29@@oe@16-12-2010 1019402003@GENIA Treebank@formal@@1@S@The tissue from both patients generated a polyclonal pattern of X chromosome inactivation of the human androgen receptor gene.@@@@1@20@@oe@16-12-2010 1019402004@GENIA Treebank@formal@@1@S@This finding supports a polyclonal reactive process as the underlying etiology for palmar fibromatosis.@@@@1@15@@oe@16-12-2010 1019418401@GENIA Treebank@formal@@1@S@Activation of NF-kappaB in Mycobacterium tuberculosis- induced interleukin-2 receptor expression in mononuclear phagocytes.@@@@1@13@@oe@16-12-2010 1019418402@GENIA Treebank@formal@@1@S@Soluble interleukin-2 receptor-alpha (IL-2Ralpha) has been reported to be increased in the sera of patients with advanced tuberculosis, and levels decline after therapy in accordance with improvement of radiologic findings.@@@@1@34@@oe@16-12-2010 1019418403@GENIA Treebank@formal@@1@S@We investigated expression of the IL-2Ralpha in bronchoalveolar lavage (BAL) cells in active pulmonary tuberculosis, and evaluated the mechanism Mycobacterium tuberculosis induces in the IL-2Ralpha using the THP-1 mononuclear phagocyte cell line.@@@@1@36@@oe@16-12-2010 1019418404@GENIA Treebank@formal@@1@S@We found IL-2Ralpha expression to be increased in BAL cells from involved sites of active pulmonary tuberculosis.@@@@1@18@@oe@16-12-2010 1019418405@GENIA Treebank@formal@@1@S@Expression of the alpha-chain of IL-2Ralpha on peripheral blood monocytes (PBM) was induced by M. tuberculosis by flow cytometry evaluation.@@@@1@23@@oe@16-12-2010 1019418406@GENIA Treebank@formal@@1@S@Northern analysis demonstrated increased IL-2Ralpha gene expression after stimulation with M. tuberculosis which was further induced by interferon-gamma (IFN-gamma).@@@@1@22@@oe@16-12-2010 1019418407@GENIA Treebank@formal@@1@S@The IL-2Ralpha promoter containing the nuclear factor kappa B (NF-kappaB) site was transcriptionally induced by M. tuberculosis and this NF-kappaB site could confer inducibility to a heterologous herpes thymidine kinase (TK) promoter by M. tuberculosis.@@@@1@40@@oe@16-12-2010 1019418408@GENIA Treebank@formal@@1@S@Electrophoretic mobility shift assays (EMSAs) revealed specific binding of nuclear protein to the NF-kappaB site upon induction with M. tuberculosis.@@@@1@23@@oe@16-12-2010 1019418409@GENIA Treebank@formal@@1@S@Using antibodies against the p50 and p65 subunits of NF-kappaB in EMSAs, the involvement of both p50 and p65 proteins was further demonstrated.@@@@1@25@@oe@16-12-2010 1019418410@GENIA Treebank@formal@@1@S@Functional expression of the IL-2Ralpha on mononuclear phagocytes in M. tuberculosis infection may play an important immunomodulatory role in the host response.@@@@1@23@@oe@16-12-2010 1019444301@GENIA Treebank@formal@@1@S@Regulation of the megakaryocytic glycoprotein IX promoter by the oncogenic Ets transcription factor Fli-1.@@@@1@15@@oe@16-12-2010 1019444302@GENIA Treebank@formal@@1@S@Glycoprotein (GP) IX is a subunit of the von Willebrand receptor, GPIb-V-IX, which mediates adhesion of platelets to the subendothelium of damaged blood vessels.@@@@1@29@@oe@16-12-2010 1019444303@GENIA Treebank@formal@@1@S@Previous characterization of the GPIX promoter identified a functional Ets site that, when disrupted, reduced promoter activity.@@@@1@20@@oe@16-12-2010 1019444304@GENIA Treebank@formal@@1@S@However, the Ets protein(s) that regulated GPIX promoter expression was unknown.@@@@1@16@@oe@16-12-2010 1019444305@GENIA Treebank@formal@@1@S@In this study, transient cotransfection of several GPIX promoter/reporter constructs into 293T kidney fibroblasts with a Fli-1 expression vector shows that the oncogenic protein Fli-1 can transactivate the GPIX promoter when an intact GPIX Ets site is present.@@@@1@40@@oe@16-12-2010 1019444306@GENIA Treebank@formal@@1@S@In addition, Fli-1 binding of the GPIX Ets site was identified in antibody supershift experiments in nuclear extracts derived from hematopoietic human erythroleukemia cells.@@@@1@26@@oe@16-12-2010 1019444307@GENIA Treebank@formal@@1@S@Comparative studies showed that Fli-1 was also able to transactivate the GPIbalpha and, to a lesser extent, the GPIIb promoter.@@@@1@23@@oe@16-12-2010 1019444308@GENIA Treebank@formal@@1@S@Immunoblot analysis identified Fli-1 protein in lysates derived from platelets.@@@@1@11@@oe@16-12-2010 1019444309@GENIA Treebank@formal@@1@S@In addition, expression of Fli-1 was identified immunohistochemically in megakaryocytes derived from CD34(+) cells treated with the megakaryocyte differentiation and proliferation factor, thrombopoietin.@@@@1@26@@oe@16-12-2010 1019444310@GENIA Treebank@formal@@1@S@These results suggest that Fli-1 is likely to regulate lineage-specific genes during megakaryocytopoiesis.@@@@1@14@@oe@16-12-2010 1019537901@GENIA Treebank@formal@@1@S@Transient pseudo-hypoaldosteronism following resection of the ileum: normal level of lymphocytic aldosterone receptors outside the acute phase.@@@@1@19@@oe@16-12-2010 1019537902@GENIA Treebank@formal@@1@S@Pseudo-hypoaldosteronism (PHA) is due to mineralocorticoid resistance and manifests as hyponatremia and hyperkalemia with increased plasma aldosterone levels.@@@@1@21@@oe@16-12-2010 1019537903@GENIA Treebank@formal@@1@S@It may be familial or secondary to abnormal renal sodium handling.@@@@1@12@@oe@16-12-2010 1019537904@GENIA Treebank@formal@@1@S@We report the case of a 54-year-old woman with multifocal cancer of the colon, who developed PHA after subtotal colectomy, ileal resection and jejunostomy.@@@@1@27@@oe@16-12-2010 1019537905@GENIA Treebank@formal@@1@S@She was treated with 6 g of salt daily to prevent dehydration, which she stopped herself because of reduced fecal losses.@@@@1@23@@oe@16-12-2010 1019537906@GENIA Treebank@formal@@1@S@One month later she was admitted with signs of acute adrenal failure, i.e. fatigue, severe nausea, blood pressure of 80/60 mmHg, extracellular dehydration, hyponatremia (118 mmol/l); hyperkalemia (7.6 mmol/l), increased blood urea nitrogen (BUN) (200 mg/dl) and creatininemia (2.5 mg/dl), and decreased plasma bicarbonates level (HCO3-: 16 mmol/l; N: 27-30).@@@@1@74@@oe@16-12-2010 1019537907@GENIA Treebank@formal@@1@S@However, the plasma cortisol was high (66 microg/100 ml at 10:00 h; N: 8-15) and the ACTH was normal (13 pg/ml, N: 10-60); there was a marked increase in plasma renin activity (>37 ng/ml/h; N supine <3), active renin (869 pg/ml; N supine: 1.120), aldosterone (>2000 pg/ml; N supine <150) and plasma AVP (20 pmol/l; N: 0.5-2.5).@@@@1@88@@oe@16-12-2010 1019537908@GENIA Treebank@formal@@1@S@The plasma ANH level was 38 pmol/l (N supine: 5-25).@@@@1@14@@oe@16-12-2010 1019537909@GENIA Treebank@formal@@1@S@A urinary steroidogram resulted in highly elevated tetrahydrocortisol (THF: 13.3 mg/24h; N: 1.4+/-0.8) with no increase in tetrahydrocortisone (THE: 3.16 mg/24h; N: 2.7+/-2.0) excretion, and with low THE/THF (0.24; N: 1.87+/-0.36) and alpha THF/THF (0.35; N: 0.92+/-0.42) ratios.@@@@1@58@@oe@16-12-2010 1019537910@GENIA Treebank@formal@@1@S@The number of mineralocorticoid receptors in mononuclear leukocytes was in the lower normal range for age, while the number of glucocorticoid receptors was reduced.@@@@1@26@@oe@16-12-2010 1019537911@GENIA Treebank@formal@@1@S@Small-bowel resection in ileostomized patients causes excessive fecal sodium losses and results in chronic sodium depletion with contraction of the plasma volume and severe secondary hyperaldosteronism.@@@@1@27@@oe@16-12-2010 1019537912@GENIA Treebank@formal@@1@S@Nevertheless, this hyperaldosteronism may be associated with hyponatremia and hyperkalemia suggesting PHA related to the major importance of the colon for the absorption of sodium.@@@@1@27@@oe@16-12-2010 1019537913@GENIA Treebank@formal@@1@S@In conclusion, this case report emphasizes 1) the possibility of a syndrome of acquired PHA with severe hyperkalemia after resection of the ileum and colon responding to oral salt supplementation; 2) the major increase in AVP and the small increase in ANH; 3) the strong increase in urinary THF with low THE/THF and alpha THF/THF ratios; 4) the normal number of lymphocytic mineralocorticoid receptors outside the acute episode.@@@@1@77@@oe@16-12-2010 1019542801@GENIA Treebank@formal@@1@S@The Epstein-Barr virus nuclear antigen 2 (EBNA2), a protein required for B lymphocyte immortalization, induces the synthesis of type I interferon in Burkitt's lymphoma cell lines.@@@@1@32@@oe@16-12-2010 1019542802@GENIA Treebank@formal@@1@S@Epstein-Barr virus nuclear antigen 2 (EBNA2), a protein involved in cell transformation, interferes with the cellular response to type I interferons (IFN-alpha/beta).@@@@1@29@@oe@16-12-2010 1019542803@GENIA Treebank@formal@@1@S@We investigated the function of conditionally expressed EBNA2 in the context of the IFN response in Burkitt's lymphoma cell lines.@@@@1@22@@oe@16-12-2010 1019542804@GENIA Treebank@formal@@1@S@Expression of EBNA2 led to the transcriptional activation of both endogenous or transfected IFN-stimulated genes (ISGs), genes which contain within their promoters either the interferon-stimulated response element (ISRE) or the gamma interferon activation site (GAS).@@@@1@43@@oe@16-12-2010 1019542805@GENIA Treebank@formal@@1@S@In search of a molecular mechanism for the transcriptional induction of ISGs, we observed an EBNA2-dependent synthesis of IFN-beta mRNA at low levels and the secretion of low amounts of IFN.@@@@1@33@@oe@16-12-2010 1019542806@GENIA Treebank@formal@@1@S@A transfected IFN-beta promoter responded to EBNA2 activation, and a sequence closely resembling a RBP-Jkappa binding site was pinpointed as a potential target of EBNA2 activity.@@@@1@28@@oe@16-12-2010 1019542807@GENIA Treebank@formal@@1@S@EBNA2-dependent transcriptional induction of the IFN-beta promoter occurred in EBV-negative Burkitt's lymphoma cells, indicating that other EBV genes were not required for the induction of IFN-beta synthesis.@@@@1@30@@oe@16-12-2010 1019628601@GENIA Treebank@formal@@1@S@Role of cellular tumor necrosis factor receptor-associated factors in NF-kappaB activation and lymphocyte transformation by herpesvirus Saimiri STP.@@@@1@19@@oe@16-12-2010 1019628602@GENIA Treebank@formal@@1@S@The STP oncoproteins of the herpesvirus saimiri (HVS) subgroup A strain 11 and subgroup C strain 488 are now found to be stably associated with tumor necrosis factor receptor-associated factor (TRAF) 1, 2, or 3.@@@@1@42@@oe@16-12-2010 1019628603@GENIA Treebank@formal@@1@S@Mutational analyses identified residues of PXQXT/S in STP-A11 as critical for TRAF association.@@@@1@14@@oe@16-12-2010 1019628604@GENIA Treebank@formal@@1@S@In addition, a somewhat divergent region of STP-C488 is critical for TRAF association.@@@@1@15@@oe@16-12-2010 1019628605@GENIA Treebank@formal@@1@S@Mutational analysis also revealed that STP-C488 induced NF-kappaB activation that was correlated with its ability to associate with TRAFs.@@@@1@20@@oe@16-12-2010 1019628606@GENIA Treebank@formal@@1@S@The HVS STP-C488 P10-->R mutant was deficient in human T-lymphocyte transformation to interleukin-2-independent growth but showed wild-type phenotype for marmoset T-lymphocyte transformation in vitro and in vivo.@@@@1@30@@oe@16-12-2010 1019628607@GENIA Treebank@formal@@1@S@The STP-C488 P10-->R mutant was also defective in Rat-1 fibroblast transformation, and fibroblast cell transformation was blocked by a TRAF2 dominant-negative mutant.@@@@1@26@@oe@16-12-2010 1019628608@GENIA Treebank@formal@@1@S@These data implicate TRAFs in STP-C488-mediated transformation of human lymphocytes and rodent fibroblasts.@@@@1@14@@oe@16-12-2010 1019628609@GENIA Treebank@formal@@1@S@Other factors are implicated in immortalization of common marmoset T lymphocytes and may also be critical in the transformation of human lymphocytes and rodent fibroblasts.@@@@1@26@@oe@16-12-2010 1019773101@GENIA Treebank@formal@@1@S@Studies into the effect of tyrosine phosphatase inhibitor phenylarsine oxide on NFkappaB activation in T lymphocytes during aging: evidence for altered IkappaB-alpha phosphorylation and degradation.@@@@1@27@@oe@16-12-2010 1019773102@GENIA Treebank@formal@@1@S@Nuclear Factor kappa B (NFkappaB) is a critical regulator of several genes involved in immune and inflammatory responses.@@@@1@21@@oe@16-12-2010 1019773103@GENIA Treebank@formal@@1@S@Treatment of T cells with a variety of stimuli, including TNF-alpha, leads to the translocation of the active p65-50 heterodimer to the nucleus, albeit at a lower level in T cells from the elderly.@@@@1@38@@oe@16-12-2010 1019773104@GENIA Treebank@formal@@1@S@We demonstrate here that pretreatment with PAO results in the inhibition of NFkappaB induction in TNF-alpha treated T cells, suggesting a role for PAO-sensitive phosphatase in the activation of the NFkappaB via this pathway in human T cells.@@@@1@40@@oe@16-12-2010 1019773105@GENIA Treebank@formal@@1@S@Furthermore, it demonstrates that aging does not influence the sensitivity of this phosphatase.@@@@1@15@@oe@16-12-2010 1019773106@GENIA Treebank@formal@@1@S@Treatment with DMP prior to treatment with PAO and TNF abolishes the inhibition induced by PAO, in T cells from both young and old donors, alike.@@@@1@29@@oe@16-12-2010 1019773107@GENIA Treebank@formal@@1@S@Finally, we demonstrate that a failure to degrade IkappaB-alpha in cytosols of TNF-treated T cells pretreated with PAO is due to its interference with the phosphorylation of IkappaB-alpha and not due to its inhibitory effect on proteasomal degradation.@@@@1@40@@oe@16-12-2010 1019773108@GENIA Treebank@formal@@1@S@These data collectively suggest that PAO interferes with the phosphorylation and the regulated degradation of IkappaB-alpha, induced by TNF, without affecting the chymotryptic activity of the proteasome, independent of age.@@@@1@34@@oe@16-12-2010 1020000701@GENIA Treebank@formal@@1@S@In vivo modulation of glucocorticoid receptor mRNA by inhaled fluticasone propionate in bronchial mucosa and blood lymphocytes in subjects with mild asthma.@@@@1@23@@oe@16-12-2010 1020000702@GENIA Treebank@formal@@1@S@BACKGROUND: In vivo regulation of the glucocorticoid receptor (GR) by glucocorticoids provides a means of modulating sensitivity of targeted cells.@@@@1@24@@oe@16-12-2010 1020000703@GENIA Treebank@formal@@1@S@OBJECTIVE: We sought to determine the in vivo modulation of GR mRNA expression by fluticasone propionate (FP) in subjects with mild asthma.@@@@1@26@@oe@16-12-2010 1020000704@GENIA Treebank@formal@@1@S@METHODS: Ten atopic asthmatic subjects were treated with FP 250 microg twice daily for 4 weeks.@@@@1@18@@oe@16-12-2010 1020000705@GENIA Treebank@formal@@1@S@Before and after treatment, the patients underwent fiberoptic bronchoscopy with endobronchial biopsy and sampling of venous blood for measurements of GR mRNA levels.@@@@1@25@@oe@16-12-2010 1020000706@GENIA Treebank@formal@@1@S@A solution hybridization assay was used for quantitative analysis of GR mRNA.@@@@1@13@@oe@16-12-2010 1020000707@GENIA Treebank@formal@@1@S@In addition, a 24-hour urinary cortisol excretion and an adrenocorticotropic hormone test before and after treatment with FP were performed.@@@@1@22@@oe@16-12-2010 1020000708@GENIA Treebank@formal@@1@S@RESULTS: A high interindividual variation in GR mRNA expression was seen.@@@@1@13@@oe@16-12-2010 1020000709@GENIA Treebank@formal@@1@S@However, we detected a significant reduction of the GR mRNA levels in the endobronchial biopsy specimens after FP treatment (36.6 +/- 23.1 and 25.0 +/- 10.9 amol GR mRNA/microg RNA, respectively; P <.01).@@@@1@40@@oe@16-12-2010 1020000710@GENIA Treebank@formal@@1@S@In the peripheral blood lymphocytes an even more striking downregulation of the GR by its cognate ligand was documented (30.3 +/- 26.5 and 8.8 +/- 5 amol GR mRNA/microg RNA, respectively; P <.001), possibly reflecting differences in glucocorticoid sensitivity between tissues.@@@@1@48@@oe@16-12-2010 1020000711@GENIA Treebank@formal@@1@S@A small but significant reduction of the 24-hour urinary cortisol excretion was observed (233 +/- 109 and 157 +/- 66 nmol/L, respectively; P <.01), whereas the feedback regulation of glucocorticoid synthesis by means of the hypothalamic-pituitary-adrenal axis as assessed by the adrenocorticotropic hormone test remained normal after treatment with FP.@@@@1@57@@oe@16-12-2010 1020000712@GENIA Treebank@formal@@1@S@CONCLUSION: The results in this study confirm the potency of the inhaled corticosteroid FP and provide evidence for a considerable tissue-specific interindividual variation in the expression of the GR.@@@@1@31@@oe@16-12-2010 1020029401@GENIA Treebank@formal@@1@S@A novel lipopolysaccharide-induced transcription factor regulating tumor necrosis factor alpha gene expression: molecular cloning, sequencing, characterization, and chromosomal assignment.@@@@1@24@@oe@16-12-2010 1020029402@GENIA Treebank@formal@@1@S@Lipopolysaccharide (LPS) is a potent stimulator of monocytes and macrophages, causing secretion of tumor necrosis factor alpha (TNF-alpha) and other inflammatory mediators.@@@@1@28@@oe@16-12-2010 1020029403@GENIA Treebank@formal@@1@S@Given the deleterious effects to the host of TNF-alpha, it has been postulated that TNF-alpha gene expression must be tightly regulated.@@@@1@23@@oe@16-12-2010 1020029404@GENIA Treebank@formal@@1@S@The nature of the nuclear factor(s) that control TNF-alpha gene transcription in humans remains obscure, although NF-kappaB has been suggested.@@@@1@25@@oe@16-12-2010 1020029405@GENIA Treebank@formal@@1@S@Our previous studies pertaining to macrophage response to LPS identified a novel DNA-binding domain located from -550 to -487 in the human TNF-alpha promoter that contains transcriptional activity, but lacks any known NF-kappaB-binding sites.@@@@1@36@@oe@16-12-2010 1020029406@GENIA Treebank@formal@@1@S@We have used this DNA fragment to isolate and purify a 60-kDa protein binding to this fragment and obtained its amino-terminal sequence, which was used to design degenerate probes to screen a cDNA library from THP-1 cells.@@@@1@39@@oe@16-12-2010 1020029407@GENIA Treebank@formal@@1@S@A novel cDNA clone (1.8 kb) was isolated and fully sequenced.@@@@1@14@@oe@16-12-2010 1020029408@GENIA Treebank@formal@@1@S@Characterization of this cDNA clone revealed that its induction was dependent on LPS activation of THP-1 cells; hence, the name LPS-induced TNF-alpha factor (LITAF).@@@@1@29@@oe@16-12-2010 1020029409@GENIA Treebank@formal@@1@S@Inhibition of LITAF mRNA expression in THP-1 cells resulted in a reduction of TNF-alpha transcripts.@@@@1@16@@oe@16-12-2010 1020029410@GENIA Treebank@formal@@1@S@In addition, high level of expression of LITAF mRNA was observed predominantly in the placenta, peripheral blood leukocytes, lymph nodes, and the spleen.@@@@1@28@@oe@16-12-2010 1020029411@GENIA Treebank@formal@@1@S@Finally, chromosomal localization using fluorescence in situ hybridization revealed that LITAF mapped to chromosome 16p12-16p13.3.@@@@1@17@@oe@16-12-2010 1020029412@GENIA Treebank@formal@@1@S@Together, these findings suggest that LITAF plays an important role in the activation of the human TNF-alpha gene and proposes a new mechanism to control TNF-alpha gene expression.@@@@1@30@@oe@16-12-2010 1020189901@GENIA Treebank@formal@@1@S@p38 mitogen-activated protein kinase mediates signal integration of TCR/CD28 costimulation in primary murine T cells.@@@@1@16@@oe@16-12-2010 1020189902@GENIA Treebank@formal@@1@S@Optimal T cell activation requires two signals, one generated by TCR and another by the CD28 costimulatory receptor.@@@@1@20@@oe@16-12-2010 1020189903@GENIA Treebank@formal@@1@S@In this study, we investigated the regulation of costimulation-induced mitogen-activated protein kinase (MAPK) activation in primary mouse T cells.@@@@1@23@@oe@16-12-2010 1020189904@GENIA Treebank@formal@@1@S@In contrast to that reported for human Jurkat T cells, we found that p38 MAPK, but not Jun NH2-terminal kinase (JNK), is weakly activated upon stimulation with either anti-CD3 or anti-CD28 in murine thymocytes and splenic T cells.@@@@1@44@@oe@16-12-2010 1020189905@GENIA Treebank@formal@@1@S@However, p38 MAPK is activated strongly and synergistically by either CD3/CD28 coligation or PMA/Ca2+ ionophore stimulation, which mimics TCR-CD3/CD28-mediated signaling.@@@@1@23@@oe@16-12-2010 1020189906@GENIA Treebank@formal@@1@S@Activation of p38 MAPK correlates closely with the stimulation of T cell proliferation.@@@@1@14@@oe@16-12-2010 1020189907@GENIA Treebank@formal@@1@S@In contrast, PMA-induced JNK activation is inhibited by Ca2+ ionophore.@@@@1@12@@oe@16-12-2010 1020189908@GENIA Treebank@formal@@1@S@T cell proliferation and production of IL-2, IL-4, and IFN-gamma induced by both CD3 and CD3/CD28 ligation and the nuclear expression of the c-Jun and ATF-2 proteins are each blocked by the p38 MAPK inhibitor SB203580.@@@@1@39@@oe@16-12-2010 1020189909@GENIA Treebank@formal@@1@S@Our findings demonstrate that p38 MAPK 1) plays an important role in signal integration during costimulation of primary mouse T cells, 2) may be involved in the induction of c-Jun activation and augmentation of AP-1 transcriptional activity, and 3) regulates whether T cells enter a state of functional unresponsiveness.@@@@1@55@@oe@16-12-2010 1020192901@GENIA Treebank@formal@@1@S@Engagement of natural cytotoxicity programs regulates AP-1 expression in the NKL human NK cell line.@@@@1@16@@oe@16-12-2010 1020192902@GENIA Treebank@formal@@1@S@NK cell cytotoxicity is a fast and efficient mechanism of target cell lysis.@@@@1@14@@oe@16-12-2010 1020192903@GENIA Treebank@formal@@1@S@Using transcription analysis, such as multiplex messenger assays, we show here that natural cytotoxicity exerted by the human NKL cell line correlates with mRNA accumulation of very early activator protein (AP)-1 transcription factor genes such as JunB, FosB and c-Fos.@@@@1@47@@oe@16-12-2010 1020192904@GENIA Treebank@formal@@1@S@In addition, DNA-binding activities of Jun-Fos heterodimers were observed by electrophoretic mobility shift assays during the course of natural cytotoxicity.@@@@1@22@@oe@16-12-2010 1020192905@GENIA Treebank@formal@@1@S@Interaction between immunoglobulin-like transcript-2/leukocyte Ig-like receptor 1 on NKL cells and HLA-B27 on target cells leads to an impairment of NKL natural cytotoxicity, which correlates with an absence of JunB, FosB, and c-Fos transcription, as well as an absence of their DNA-binding activity.@@@@1@48@@oe@16-12-2010 1020192906@GENIA Treebank@formal@@1@S@Our studies thus indicate that, despite the rapidity of NK cell-mediated lysis, AP-1 transcription factor is activated during the early stage of NK cell cytolytic programs and that engagement of NK cell inhibitory receptors for MHC class I molecules impairs the very early activation of AP-1.@@@@1@49@@oe@16-12-2010 1020198401@GENIA Treebank@formal@@1@S@The functional synergy between IL-12 and IL-2 involves p38 mitogen-activated protein kinase and is associated with the augmentation of STAT serine phosphorylation.@@@@1@23@@oe@16-12-2010 1020198402@GENIA Treebank@formal@@1@S@IL-12 and IL-2 can stimulate mitogen- or CD3-activated T cells to proliferate, produce IFN-gamma, and kill tumor cells.@@@@1@21@@oe@16-12-2010 1020198403@GENIA Treebank@formal@@1@S@The magnitude of these functional responses is greatly augmented when T cells are activated by the combination of IL-12 and IL-2.@@@@1@22@@oe@16-12-2010 1020198404@GENIA Treebank@formal@@1@S@Although peripheral blood T cells are largely unresponsive to these cytokines without prior activation, a small subset of CD8+ T cells (CD8+CD18bright) is strongly activated by the combination of IL-12 and IL-2.@@@@1@36@@oe@16-12-2010 1020198405@GENIA Treebank@formal@@1@S@In this report we show that the functional synergy between IL-12 and IL-2 in CD8+CD18bright T cells correlates with the activation of the stress kinases, p38 mitogen-activated protein (MAP) kinase and stress-activated protein kinase (SAPK)/Jun N-terminal kinase, but not with the activation of the extracellular signal-regulated kinases.@@@@1@55@@oe@16-12-2010 1020198406@GENIA Treebank@formal@@1@S@The functional synergy between IL-2 and IL-12 is also associated with a prominent increase in STAT1 and STAT3 serine phosphorylation over that observed with IL-12 or IL-2 alone.@@@@1@29@@oe@16-12-2010 1020198407@GENIA Treebank@formal@@1@S@By contrast, STAT tyrosine phosphorylation is not augmented over that seen with either cytokine alone.@@@@1@17@@oe@16-12-2010 1020198408@GENIA Treebank@formal@@1@S@A specific inhibitor of p38 MAP kinase completely inhibits the serine phosphorylation of STAT1 and STAT3 induced by IL-12 and IL-2 and abrogates the functional synergy between IL-12 and IL-2 without affecting STAT tyrosine phosphorylation.@@@@1@36@@oe@16-12-2010 1020198409@GENIA Treebank@formal@@1@S@This suggests that p38 MAP kinase may play an important role in regulating STAT serine phosphorylation in response to the combination of IL-12 and IL-2.@@@@1@26@@oe@16-12-2010 1020198410@GENIA Treebank@formal@@1@S@Furthermore, these findings indicate that the optimal activation of T cells by IL-12 and IL-2 may depend on an interaction between the p38 MAP kinase and Janus kinase/STAT signaling pathways.@@@@1@32@@oe@16-12-2010 1020202401@GENIA Treebank@formal@@1@S@Human cytomegalovirus binding to human monocytes induces immunoregulatory gene expression.@@@@1@11@@oe@16-12-2010 1020202402@GENIA Treebank@formal@@1@S@To continue our investigation of the cellular events that occur following human CMV (HCMV) infection, we focused on the regulation of cellular activation following viral binding to human monocytes.@@@@1@33@@oe@16-12-2010 1020202403@GENIA Treebank@formal@@1@S@First, we showed that viral binding induced a number of immunoregulatory genes (IL-1beta, A20, NF-kappaB-p105/p50, and IkappaBalpha) in unactivated monocytes and that neutralizing Abs to the major HCMV glycoproteins, gB (UL55) and gH (UL75), inhibited the induction of these genes.@@@@1@53@@oe@16-12-2010 1020202404@GENIA Treebank@formal@@1@S@Next, we demonstrated that these viral ligands directly up-regulated monocyte gene expression upon their binding to their appropriate cellular receptors.@@@@1@22@@oe@16-12-2010 1020202405@GENIA Treebank@formal@@1@S@We then investigated if HCMV binding also resulted in the translation and secretion of cytokines.@@@@1@16@@oe@16-12-2010 1020202406@GENIA Treebank@formal@@1@S@Our results showed that HCMV binding to monocytes resulted in the production and release of IL-1beta protein.@@@@1@18@@oe@16-12-2010 1020202407@GENIA Treebank@formal@@1@S@Because these induced gene products have NF-kappaB sites in their promoter regions, we next examined whether there was an up-regulation of nuclear NF-kappaB levels.@@@@1@26@@oe@16-12-2010 1020202408@GENIA Treebank@formal@@1@S@These experiments showed that, in fact, NF-kappaB was translocated to the nucleus following viral binding or purified viral ligand binding.@@@@1@23@@oe@16-12-2010 1020202409@GENIA Treebank@formal@@1@S@Changes in IkappaBalpha levels correlated with the changes in NF-kappaB translocation.@@@@1@12@@oe@16-12-2010 1020202410@GENIA Treebank@formal@@1@S@Lastly, we demonstrated that p38 kinase activity played a central role in IL-1beta production and that it was rapidly up-regulated following infection.@@@@1@24@@oe@16-12-2010 1020202411@GENIA Treebank@formal@@1@S@These results support our hypothesis that HCMV initiates a signal transduction pathway that leads to monocyte activation and pinpoints a potential mechanism whereby HCMV infection of monocytes can result in profound pathogenesis, especially in chronic inflammatory-type conditions.@@@@1@39@@oe@16-12-2010 1020202701@GENIA Treebank@formal@@1@S@Signal transduction pathways activated in endothelial cells following infection with Chlamydia pneumoniae.@@@@1@13@@oe@16-12-2010 1020202702@GENIA Treebank@formal@@1@S@Chlamydia pneumoniae is an important respiratory pathogen.@@@@1@8@@oe@16-12-2010 1020202703@GENIA Treebank@formal@@1@S@Recently, its presence has been demonstrated in atherosclerotic lesions.@@@@1@11@@oe@16-12-2010 1020202704@GENIA Treebank@formal@@1@S@In this study, we characterized C. pneumoniae-mediated activation of endothelial cells and demonstrated an enhanced expression of endothelial adhesion molecules followed by subsequent rolling, adhesion, and transmigration of leukocytes (monocytes, granulocytes).@@@@1@38@@oe@16-12-2010 1020202705@GENIA Treebank@formal@@1@S@These effects were blocked by mAbs against endothelial and/or leukocyte adhesion molecules (beta1 and beta2 integrins).@@@@1@19@@oe@16-12-2010 1020202706@GENIA Treebank@formal@@1@S@Additionally, activation of different signal transduction pathways in C. pneumoniae-infected endothelial cells was shown: protein tyrosine phosphorylation, up-regulation of phosphorylated p42/p44 mitogen-activated protein kinase, and NF-kappaB activation/translocation occurred within 10-15 min.@@@@1@36@@oe@16-12-2010 1020202707@GENIA Treebank@formal@@1@S@Increased mRNA and surface expression of E-selectin, ICAM-1, and VCAM-1 were noted within hours.@@@@1@17@@oe@16-12-2010 1020202708@GENIA Treebank@formal@@1@S@Thus, C. pneumoniae triggers a cascade of events that could lead to endothelial activation, inflammation, and thrombosis, which in turn may result in or may promote atherosclerosis.@@@@1@32@@oe@16-12-2010 1020203401@GENIA Treebank@formal@@1@S@Extracellular-regulated kinase 1/2, Jun N-terminal kinase, and c-Jun are involved in NF-kappa B-dependent IL-6 expression in human monocytes.@@@@1@21@@oe@16-12-2010 1020203402@GENIA Treebank@formal@@1@S@In the present study we investigated the possible involvement of the mitogen-activated protein kinase family members extracellular-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) in mediating IL-6 gene expression in human monocytes, in particular their role in enhancing NF-kappa B activity.@@@@1@48@@oe@16-12-2010 1020203403@GENIA Treebank@formal@@1@S@Freshly isolated monocytes treated with the protein phosphatase inhibitor okadaic acid secreted high levels of IL-6 protein, which coincided with enhanced binding activity of NF-kappa B as well as with phosphorylation and activation of the ERK1/2 and JNK proteins.@@@@1@41@@oe@16-12-2010 1020203404@GENIA Treebank@formal@@1@S@The ERK pathway-specific inhibitor PD98059 inhibited IL-6 secretion from monocytes.@@@@1@11@@oe@16-12-2010 1020203405@GENIA Treebank@formal@@1@S@Transient overexpression of inactive mutants of either Raf-1 or JNK1 showed that both pathways were involved in kappa B-dependent IL-6 promoter activity.@@@@1@23@@oe@16-12-2010 1020203406@GENIA Treebank@formal@@1@S@By using PD98059, we demonstrated that the Raf1/MEK1/ERK1/2 pathway did not affect the DNA binding of NF-kappa B but, rather, acted at the level of transcriptional activity of NF-kappa B.@@@@1@34@@oe@16-12-2010 1020203407@GENIA Treebank@formal@@1@S@Interestingly, it was shown that NF-kappa B-mediated gene transcription, both in the context of the IL-6 promoter as well as on its own, was dependent on both serine kinase activity and interaction with c-Jun protein.@@@@1@39@@oe@16-12-2010 1020203408@GENIA Treebank@formal@@1@S@We conclude that okadaic acid-induced IL-6 gene expression is at least partly mediated through the ERK1/2 and JNK pathway-dependent activation of NF-kappa B transcriptional capacity.@@@@1@26@@oe@16-12-2010 1020203409@GENIA Treebank@formal@@1@S@Our results suggest that the JNK pathway may regulate NF-kappa B-mediated gene transcription through its phosphorylation and activation of c-Jun.@@@@1@21@@oe@16-12-2010 1020217801@GENIA Treebank@formal@@1@S@Differential induction of interferon (IFN)-inducible protein 10 following differentiation of a monocyte, macrophage cell lineage is related to the changes of nuclear proteins bound to IFN stimulus response element and kappaB sites.@@@@1@37@@oe@16-12-2010 1020217802@GENIA Treebank@formal@@1@S@We examined chemokine gene expression following the differentiation of a monocyte, macrophage cell lineage.@@@@1@16@@oe@16-12-2010 1020217803@GENIA Treebank@formal@@1@S@The human monoblastic cell line, U937 was differentiated to macrophages by the treatment with either phorbol 12-myristate 13-acetate (PMA), retinoic acid (RA), or vitamin D3 (VitD3).@@@@1@36@@oe@16-12-2010 1020217804@GENIA Treebank@formal@@1@S@The gene expression of interferon (IFN)-inducible protein 10 (IP-10) (a CXC chemokine) was markedly augmented by the IFNgamma treatment in PMA- or RA-differentiated U937 cells, but only marginally in undifferentiated or VitD3-treated cells.@@@@1@42@@oe@16-12-2010 1020217805@GENIA Treebank@formal@@1@S@In contrast, another inducible gene expression of monocyte chemotactic protein-1 (a CC chemokine) and the activation of the transcriptional factor (FcRFgamma) bound to the gamma response region were similarly or less abundantly induced by IFNgamma treatment in PMA- or RA-differentiated U937 cells, indicating that increased IP-10 mRNA induction was not due to the augmented ability of the cells to respond to the presence of IFNgamma.@@@@1@72@@oe@16-12-2010 1020217806@GENIA Treebank@formal@@1@S@Increased expression of IFNgamma-induced IP-10 mRNA following the differentiation of U937 cells was mediated largely by augmented transcriptional activity of the gene and was related to differentiation-dependent changes of the proteins bound to IFN stimulus response element (ISRE) and kB sites, suggesting that these nuclear proteins may determine the IP-10 mRNA inducibility by IFNgamma.@@@@1@58@@oe@16-12-2010 1020293701@GENIA Treebank@formal@@1@S@Fludarabine-induced immunosuppression is associated with inhibition of STAT1 signaling.@@@@1@10@@oe@16-12-2010 1020293702@GENIA Treebank@formal@@1@S@Fludarabine is a nucleoside analog used in the treatment of hematologic malignancies that can induce severe and prolonged immunosuppression.@@@@1@20@@oe@16-12-2010 1020293703@GENIA Treebank@formal@@1@S@Although it can be incorporated into the DNA of dividing cells, fludarabine is also a potent inhibitor of cells with a low growth fraction, thus it must have other mechanisms of action.@@@@1@35@@oe@16-12-2010 1020293704@GENIA Treebank@formal@@1@S@STAT1, which is activated in response to many lymphocyte-activating cytokines including the interferons, is essential for cell-mediated immunity, as the absence of this protein is associated with prominent defects in the ability to control viral infections.@@@@1@40@@oe@16-12-2010 1020293705@GENIA Treebank@formal@@1@S@Here we show that fludarabine, but not the immunosuppressant cyclosporine A, inhibits the cytokine-induced activation of STAT1 and STAT1-dependent gene transcription in normal resting or activated lymphocytes.@@@@1@30@@oe@16-12-2010 1020293706@GENIA Treebank@formal@@1@S@Fludarabine caused a specific depletion of STAT1 protein (and mRNA) but not of other STATs.@@@@1@18@@oe@16-12-2010 1020293707@GENIA Treebank@formal@@1@S@This loss of STAT1 was also seen in cells from patients treated with fludarabine in vivo.@@@@1@17@@oe@16-12-2010 1020293708@GENIA Treebank@formal@@1@S@Brief exposure to fludarabine led to a sustained loss of STAT1, analogous to the prolonged period of immunosuppression induced by exposure to the drug in vivo.@@@@1@28@@oe@16-12-2010 1020293709@GENIA Treebank@formal@@1@S@Thus, STAT1 may be a useful target in the development of new immunosuppressive and antineoplastic agents.@@@@1@18@@oe@16-12-2010 1020357701@GENIA Treebank@formal@@1@S@Suppressive effects of anti-inflammatory agents on human endothelial cell activation and induction of heat shock proteins.@@@@1@17@@oe@16-12-2010 1020357702@GENIA Treebank@formal@@1@S@BACKGROUND: Studies from our laboratory have shown that the earliest stages of atherosclerosis may be mediated by an autoimmune reaction against heat shock protein 60 (Hsp60).@@@@1@30@@oe@16-12-2010 1020357703@GENIA Treebank@formal@@1@S@The interactions of Hsp60-specific T cells with arterial endothelial cells (EC) require expression of both Hsp60 and certain adhesion molecules shown to be induced simultaneously in EC by mechanical and other types of stress.@@@@1@37@@oe@16-12-2010 1020357704@GENIA Treebank@formal@@1@S@Recently, it was shown that suppression of T cell-mediated immune responses by cyclosporin A (CyA) enhanced atherosclerotic lesion formation in mice.@@@@1@25@@oe@16-12-2010 1020357705@GENIA Treebank@formal@@1@S@In contrast, aspirin was found to lower the risk of myocardial infarction in men.@@@@1@16@@oe@16-12-2010 1020357706@GENIA Treebank@formal@@1@S@These conflicting observations may be due to different effects of anti-inflammatory agents on adhesion molecule and Hsp expression in EC, respectively.@@@@1@23@@oe@16-12-2010 1020357707@GENIA Treebank@formal@@1@S@MATERIAL AND METHODS: In the present study, we analyzed the effects of CyA, aspirin, and indomethacin on T cell proliferation using a proliferation assay.@@@@1@29@@oe@16-12-2010 1020357708@GENIA Treebank@formal@@1@S@To explore the expression of adhesion molecules, monocyte chemoattractant protein-1 (MCP-1), and Hsp60 in human umbilical vein endothelial cells (HUVECs), Northern blot analyses were used.@@@@1@33@@oe@16-12-2010 1020357709@GENIA Treebank@formal@@1@S@To examine the activation status of the transcription factors nuclear factor kappaB (NF-kappaB) and heat shock factor-1 (HSF-1), electrophoretic mobility shift assays were performed.@@@@1@30@@oe@16-12-2010 1020357710@GENIA Treebank@formal@@1@S@RESULTS: With the exception of indomethacin, the used immunosuppressive and anti-inflammatory agents significantly inhibited T cell proliferation in response to influenza virus antigen in a dose-dependent manner.@@@@1@30@@oe@16-12-2010 1020357711@GENIA Treebank@formal@@1@S@Interestingly, CyA and indomethacin did not suppress tumor necrosis factor-alpha (TNF-alpha)-induced adhesion molecule expression on HUVECs, whereas aspirin had an inhibitory effect.@@@@1@28@@oe@16-12-2010 1020357712@GENIA Treebank@formal@@1@S@These observations correlated with the modulation of NF-kappaB activity in EC.@@@@1@12@@oe@16-12-2010 1020357713@GENIA Treebank@formal@@1@S@All agents tested induced expression of Hsp60 6 hr after application.@@@@1@12@@oe@16-12-2010 1020357714@GENIA Treebank@formal@@1@S@In addition, aspirin and indomethacin, but not CyA, induced Hsp70 expression in HUVECs that correlated with induction of HSF-1 activity.@@@@1@24@@oe@16-12-2010 1020357715@GENIA Treebank@formal@@1@S@CONCLUSION: Our results show that the tested agents (except indomethacin) are inhibitors of the T cell-mediated immune response, as expected, that aspirin is an effective suppressor of adhesion molecule expression, and that all three agents can induce Hsp60 in HUVECs.@@@@1@47@@oe@16-12-2010 1020357716@GENIA Treebank@formal@@1@S@These data provide the molecular basis for the notion that (1) part of the anti-atherogenic effect of aspirin may be due to the prevention of the adhesion of sensitized T cells to stressed EC; (2) that part of the atherosclerosis-promoting effect of CyA may be due to its potential as an inducer of Hsp60 expression and its inability to down-regulate adhesion molecule expression on EC; and (3) that down-regulation of MCP-1 expression by aspirin may result in decreased recruitment of monocytes into the arterial intima beneath stressed EC.@@@@1@97@@oe@16-12-2010 1020648001@GENIA Treebank@formal@@1@S@Amelioration of rat cerulein pancreatitis by guamerin-derived peptide, a novel elastase inhibitor.@@@@1@14@@oe@16-12-2010 1020648002@GENIA Treebank@formal@@1@S@Increased activity of various proteases is observed in both human and experimental pancreatitis; however, the information on the effects of specific protease inhibitors on the disease is limited.@@@@1@31@@oe@16-12-2010 1020648003@GENIA Treebank@formal@@1@S@In this study we show that a novel elastase inhibitor, guamerin-derived synthetic peptide (GDSP), improves the parameters of cerulein-induced acute pancreatitis in the rat.@@@@1@29@@oe@16-12-2010 1020648004@GENIA Treebank@formal@@1@S@The effects of GDSP on pancreatic weight, serum amylase and lipase, morphologic changes in the pancreas, neutrophil infiltration, and nuclear factor KB (NF-KB) activation were measured in rats infused with supramaximal dose of cerulein (5 (g/kg/h) for 6 h.@@@@1@49@@oe@16-12-2010 1020648005@GENIA Treebank@formal@@1@S@The effects of GDSP were also measured on superoxide formation by activated human neutrophils.@@@@1@15@@oe@16-12-2010 1020648006@GENIA Treebank@formal@@1@S@The effects of GDSP were compared with those of another elastase inhibitor, elastatinal.@@@@1@15@@oe@16-12-2010 1020648007@GENIA Treebank@formal@@1@S@GDSP significantly inhibited edema formation, neutrophil infiltration, acinar cell damage, and plasma lipase and amylase increases caused by cerulein.@@@@1@23@@oe@16-12-2010 1020648008@GENIA Treebank@formal@@1@S@GDSP also completely inhibited superoxide formation in the human neutrophils stimulated by N-formyl-methionine-leucine-phenyl-alanine (fMLP) or 12-O-tetradecanoylphorbol-13-acetate (TPA).@@@@1@22@@oe@16-12-2010 1020648009@GENIA Treebank@formal@@1@S@Elastatinal had some of the same effects as GDSP but was less potent and effective.@@@@1@16@@oe@16-12-2010 1020648010@GENIA Treebank@formal@@1@S@These results demonstrate a beneficial effect of GDSP, a novel specific elastase inhibitor, on the development of rat cerulein pancreatitis.@@@@1@23@@oe@16-12-2010 1020698301@GENIA Treebank@formal@@1@S@Inhibition of T cell signaling by mitogen-activated protein kinase-targeted hematopoietic tyrosine phosphatase (HePTP).@@@@1@16@@oe@16-12-2010 1020698302@GENIA Treebank@formal@@1@S@Activation of T lymphocytes to produce cytokines is regulated by the counterbalance of protein-tyrosine kinases and protein-tyrosine phosphatases, many of which have a high degree of substrate specificity because of physical association with their targets.@@@@1@37@@oe@16-12-2010 1020698303@GENIA Treebank@formal@@1@S@Overexpression of hematopoietic protein-tyrosine phosphatase (HePTP) results in suppression of T lymphocyte activation as measured by T cell antigen receptor-induced activation of transcription factors binding to the 5' promoter of the interleukin-2 gene.@@@@1@36@@oe@16-12-2010 1020698304@GENIA Treebank@formal@@1@S@Efforts to pinpoint the exact site of action and specificity of HePTP in the signaling cascade revealed that HePTP acts directly on the mitogen-activated protein (MAP) kinases Erk1 and 2 and consequently reduces the magnitude and duration of their catalytic activation in intact T cells.@@@@1@48@@oe@16-12-2010 1020698305@GENIA Treebank@formal@@1@S@In contrast, HePTP had no effects on N-terminal c-Jun kinase or on events upstream of the MAP kinases.@@@@1@20@@oe@16-12-2010 1020698306@GENIA Treebank@formal@@1@S@The specificity of HePTP correlated with its physical association through its noncatalytic N terminus with Erk and another MAP kinase, p38, but not Jnk or other proteins.@@@@1@30@@oe@16-12-2010 1020698307@GENIA Treebank@formal@@1@S@We propose that HePTP plays a negative role in antigen receptor signaling by specifically regulating MAP kinases in the cytosol and at early time points of T cell activation before the activation-induced expression of nuclear dual-specific MAP kinase phosphatases.@@@@1@40@@oe@16-12-2010 1020702301@GENIA Treebank@formal@@1@S@Modulation of E2F complexes during G0 to S phase transition in human primary B-lymphocytes.@@@@1@15@@oe@16-12-2010 1020702302@GENIA Treebank@formal@@1@S@The pocket protein-E2F complexes are convergence points for cell cycle signaling.@@@@1@12@@oe@16-12-2010 1020702303@GENIA Treebank@formal@@1@S@In the present report, we identified and monitored the pocket protein-E2F complexes in human primary B-lymphocytes after activation by phorbol 12-myristate 13-acetate.@@@@1@24@@oe@16-12-2010 1020702304@GENIA Treebank@formal@@1@S@Consistent with previous data from human and mouse fibroblasts and T-lymphocytes, E2F4 and DP1 form the predominant E2F heterodimers both in G0 and G1 phases of the human B-lymphocyte cell cycle, whereas E2F1 and -3 are first detected in late G1, and their expression levels increase towards S phase.@@@@1@53@@oe@16-12-2010 1020702305@GENIA Treebank@formal@@1@S@Intriguingly, the major E2F complex that we detected in quiescent human B-lymphocytes is consisted of pRB, E2F4, and DP1.@@@@1@23@@oe@16-12-2010 1020702306@GENIA Treebank@formal@@1@S@Though the levels of DP1 and -2 increase when cells progress from G0 to S, the proportion of DP1 to DP2 remains relatively constant during the cell cycle.@@@@1@30@@oe@16-12-2010 1020702307@GENIA Treebank@formal@@1@S@We also observed an increase in electrophoretic mobility of the predominant E2F components, DP1 and E2F4, as B-lymphocytes progressed from G0 into early G1.@@@@1@27@@oe@16-12-2010 1020702308@GENIA Treebank@formal@@1@S@This increase in mobility was attributable to dephosphorylation, as lambda phosphatase treatment could convert the slower migrating forms into the corresponding faster mobility forms.@@@@1@26@@oe@16-12-2010 1020702309@GENIA Treebank@formal@@1@S@We further demonstrated that this change in phosphorylation status correlates with a decrease in DNA binding activity.@@@@1@18@@oe@16-12-2010 1020702310@GENIA Treebank@formal@@1@S@This modulation of DNA binding activity mediated through the dephosphorylation of DP1 and E2F4 could help to explain the lack of in vivo DNA footprinting in late G1 and S phases of gene promoters negatively regulated through E2F sites and suggests a novel mechanism for controlling E2F transcriptional activity during the transition from quiescence to proliferation.@@@@1@57@@oe@16-12-2010 1020706101@GENIA Treebank@formal@@1@S@Retinoid X receptor (RXR) agonist-induced activation of dominant-negative RXR-retinoic acid receptor alpha403 heterodimers is developmentally regulated during myeloid differentiation.@@@@1@22@@oe@16-12-2010 1020706102@GENIA Treebank@formal@@1@S@The multiple biologic activities of retinoic acid (RA) are mediated through RAR and retinoid X receptor (RXR) nuclear receptors that interact with specific DNA target sequences as heterodimers (RXR-RAR) or homodimers (RXR-RXR).@@@@1@41@@oe@16-12-2010 1020706103@GENIA Treebank@formal@@1@S@RA receptor activation appears critical to regulating important aspects of hematopoiesis, since transducing a COOH-terminally truncated RARalpha exhibiting dominant-negative activity (RARalpha403) into normal mouse bone marrow generates hematopoietic growth factor-dependent cell lines frozen at the multipotent progenitor (EML) or committed promyelocyte (MPRO) stages.@@@@1@51@@oe@16-12-2010 1020706104@GENIA Treebank@formal@@1@S@Nevertheless, relatively high, pharmacological concentrations of RA (1 to 10 &mgr;M) overcome these differentiation blocks and induce terminal granulocytic differentiation of the MPRO promyelocytes while potentiating interleukin-3 (IL-3)-induced commitment of EML cells to the granulocyte/monocyte lineage.@@@@1@47@@oe@16-12-2010 1020706105@GENIA Treebank@formal@@1@S@In the present study, we utilized RXR- and RAR-specific agonists and antagonists to determine how RA overcomes the dominant-negative activity of the truncated RARalpha in these different myeloid developmental stages.@@@@1@32@@oe@16-12-2010 1020706106@GENIA Treebank@formal@@1@S@Unexpectedly, we observed that an RXR-specific, rather than an RAR-specific, agonist induces terminal granulocytic differentiation of MPRO promyelocytes, and this differentiation is associated with activation of DNA response elements corresponding to RAR-RXR heterodimers rather than RXR-RXR homodimers.@@@@1@42@@oe@16-12-2010 1020706107@GENIA Treebank@formal@@1@S@This RXR agonist activity is blocked by RAR-specific antagonists, suggesting extensive cross-talk between the partners of the RXR -RARalpha403 heterodimer.@@@@1@21@@oe@16-12-2010 1020706108@GENIA Treebank@formal@@1@S@In contrast, in the more immature, multipotent EML cells we observed that this RXR-specific agonist is inactive either in potentiating IL-3-mediated commitment of EML cells to the granulocyte lineage or in transactivating RAR-RXR response elements.@@@@1@38@@oe@16-12-2010 1020706109@GENIA Treebank@formal@@1@S@RA- triggered GALdbd-RARalpha hybrid activity in these cells indicates that the multipotent EML cells harbor substantial nuclear hormone receptor coactivator activity.@@@@1@21@@oe@16-12-2010 1020706110@GENIA Treebank@formal@@1@S@However, the histone deacetylase (HDAC) inhibitor trichostatin A readily activates an RXR-RAR reporter construct in the multipotent EML cells but not in the committed MPRO promyelocytes, indicating that differences in HDAC-containing repressor complexes in these two closely related but distinct hematopoietic lineages might account for the differential activation of the RXR-RARalpha403 heterodimers that we observed at these different stages of myeloid development.@@@@1@67@@oe@16-12-2010 1020846101@GENIA Treebank@formal@@1@S@Bcl-6 expression in reactive follicular hyperplasia, follicular lymphoma, and angioimmunoblastic T-cell lymphoma with hyperplastic germinal centers: heterogeneity of intrafollicular T-cells and their altered distribution in the pathogenesis of angioimmunoblastic T-cell lymphoma.@@@@1@35@@oe@16-12-2010 1020846102@GENIA Treebank@formal@@1@S@BACKGROUND: The Bcl-6 gene product, a nuclear phosphoprotein, is expressed independently of Bcl-6 gene rearrangement.@@@@1@19@@oe@16-12-2010 1020846103@GENIA Treebank@formal@@1@S@In lymph nodes, expression of Bcl-6 protein is restricted to germinal center (GC) B-cells and 10% to 15% of CD3/CD4+ intrafollicular T cells.@@@@1@29@@oe@16-12-2010 1020846104@GENIA Treebank@formal@@1@S@Interfollicular cells are negative for Bcl-6 protein, except for rare CD3+/CD4+ T cells.@@@@1@15@@oe@16-12-2010 1020846105@GENIA Treebank@formal@@1@S@Recently, we reported cases of angioimmunoblastic T-cell lymphoma (AITL) with hyperplastic GCs (AITL/GC), and observed that borders of enlarged GCs were ill defined, with features suggestive of an outward migration of GC cells to surrounding interfollicular zones.@@@@1@45@@oe@16-12-2010 1020846106@GENIA Treebank@formal@@1@S@This prompted a study of follicular borders with Bcl-6 staining in reactive follicular hyperplasias and follicular lymphomas to compare with AITL/GC.@@@@1@22@@oe@16-12-2010 1020846107@GENIA Treebank@formal@@1@S@MATERIALS AND METHODS: Formalin-fixed paraffin sections were used for immunostaining of Bcl-6.@@@@1@14@@oe@16-12-2010 1020846108@GENIA Treebank@formal@@1@S@Six cases of AITL/GC, 12 nonspecific reactive follicular hyperplasia (FH), 7 HIV adenopathy, 10 follicular lymphoma (FL), and 8 typical AITL (ie, AITL without GC) were studied.@@@@1@39@@oe@16-12-2010 1020846109@GENIA Treebank@formal@@1@S@Double staining for Bcl-6/CD20, Bcl-6/CD3, and Bcl-6/CD57 was performed in selected cases.@@@@1@15@@oe@16-12-2010 1020846110@GENIA Treebank@formal@@1@S@RESULTS: In FH and HIV adenopathy, staining for Bcl-6 revealed densely populated GCs with well-defined and regular GC borders, whereas Bcl-6+ cells were rare in the interfollicular areas.@@@@1@32@@oe@16-12-2010 1020846111@GENIA Treebank@formal@@1@S@An occasional GC with an ill-defined border was invariably surrounded by a broad mantle zone; those with indistinct mantle zones had well-defined, regular borders.@@@@1@27@@oe@16-12-2010 1020846112@GENIA Treebank@formal@@1@S@In FL, follicles were densely populated, and their borders were irregular, with some Bcl-6+ cells in the interfollicular zones.@@@@1@23@@oe@16-12-2010 1020846113@GENIA Treebank@formal@@1@S@In AITL/GC, GCs were less dense, GC borders were ill defined and irregular, and the number of interfollicular Bcl-6+ cells was markedly increased.@@@@1@27@@oe@16-12-2010 1020846114@GENIA Treebank@formal@@1@S@Double staining revealed that these interfollicular Bcl-6+ cells in AITL/GC were Bcl6+/CD3+/CD20-/CD57- T cells.@@@@1@15@@oe@16-12-2010 1020846115@GENIA Treebank@formal@@1@S@Moreover, CD3+ intrafollicular T cells were depleted in AITL/GC, whereas they were abundant in FH.@@@@1@18@@oe@16-12-2010 1020846116@GENIA Treebank@formal@@1@S@Intrafollicular CD57+ cells did not stain for Bcl-6, and were also depleted in AITL/GC.@@@@1@16@@oe@16-12-2010 1020846117@GENIA Treebank@formal@@1@S@In typical AITL, some neoplastic cells were positive for Bcl-6, showing variable degrees of staining.@@@@1@18@@oe@16-12-2010 1020846118@GENIA Treebank@formal@@1@S@CONCLUSIONS: (1) GCs of AITL/GC differed from those of other reactive follicular hyperplasias and follicular lymphomas, and staining for Bcl-6 was useful to discern them.@@@@1@30@@oe@16-12-2010 1020846119@GENIA Treebank@formal@@1@S@(2) Intrafollicular CD3+ T cells, many of which were also positive for Bcl-6, were markedly depleted in AITL/GC, with increased interfollicular Bcl-6+/CD3+ cells, suggesting an outward migration of intrafollicular T cells in this condition.@@@@1@41@@oe@16-12-2010 1020846120@GENIA Treebank@formal@@1@S@(3) Interfollicular Bcl-6+/CD3+ cells in AITL/GC were too numerous to be accounted for by migration alone, suggesting local proliferation.@@@@1@23@@oe@16-12-2010 1020846121@GENIA Treebank@formal@@1@S@(4) Intrafollicular CD57+ cells were negative for Bcl-6, indicating heterogeneity of the intrafollicular T-cell population.@@@@1@19@@oe@16-12-2010 1020846122@GENIA Treebank@formal@@1@S@(5) Some neoplastic cells in AITL stained for Bcl-6, suggesting up-regulation of Bcl-6 expression in this tumor.@@@@1@21@@oe@16-12-2010 1020886701@GENIA Treebank@formal@@1@S@Angiotensin II activates the proinflammatory transcription factor nuclear factor-kappaB in human monocytes.@@@@1@13@@oe@16-12-2010 1020886702@GENIA Treebank@formal@@1@S@The renin-angiotensin system may contribute to the pathogenesis of atherosclerosis.@@@@1@11@@oe@16-12-2010 1020886703@GENIA Treebank@formal@@1@S@A common feature of all stages of atherosclerosis is inflammation of the vessel wall.@@@@1@15@@oe@16-12-2010 1020886704@GENIA Treebank@formal@@1@S@The transcription factor nuclear factor-kappaB (NF-kappaB) participates in most signaling pathways involved in inflammation.@@@@1@17@@oe@16-12-2010 1020886705@GENIA Treebank@formal@@1@S@This study therefore examined the effect of angiotensin (ANG) II on NF-kappaB activation in monocytic cells, a major cellular component of human atheroma, by electrophoretic mobility shift assay.@@@@1@33@@oe@16-12-2010 1020886706@GENIA Treebank@formal@@1@S@ANG II, like TNFalpha, caused rapid activation of NF-kappaB in human mononuclear cells isolated from peripheral blood by Ficoll density gradient.@@@@1@24@@oe@16-12-2010 1020886707@GENIA Treebank@formal@@1@S@This ANG II effect was blocked by the angiotensin AT1 receptor antagonist losartan.@@@@1@14@@oe@16-12-2010 1020886708@GENIA Treebank@formal@@1@S@Specificity of ANG II-induced NF-kappaB activation was ascertained by supershift and competition experiments.@@@@1@14@@oe@16-12-2010 1020886709@GENIA Treebank@formal@@1@S@Moreover, ANG II stimulated NF-kappaB activation in human monocytes, but not in lymphocytes from the same preparation.@@@@1@20@@oe@16-12-2010 1020886710@GENIA Treebank@formal@@1@S@Together, the data demonstrate the ability of the vasoactive peptide ANG II to activate inflammatory pathways in human monocytes.@@@@1@21@@oe@16-12-2010 1020886711@GENIA Treebank@formal@@1@S@Copyright 1999 Academic Press.@@@@1@5@@oe@16-12-2010 1020903601@GENIA Treebank@formal@@1@S@SHP2-interacting transmembrane adaptor protein (SIT), a novel disulfide-linked dimer regulating human T cell activation.@@@@1@18@@oe@16-12-2010 1020903602@GENIA Treebank@formal@@1@S@T lymphocytes express several low molecular weight transmembrane adaptor proteins that recruit src homology (SH)2 domain-containing intracellular molecules to the cell membrane via tyrosine-based signaling motifs.@@@@1@30@@oe@16-12-2010 1020903603@GENIA Treebank@formal@@1@S@We describe here a novel molecule of this group termed SIT (SHP2 interacting transmembrane adaptor protein).@@@@1@19@@oe@16-12-2010 1020903604@GENIA Treebank@formal@@1@S@SIT is a disulfide-linked homodimeric glycoprotein that is expressed in lymphocytes.@@@@1@12@@oe@16-12-2010 1020903605@GENIA Treebank@formal@@1@S@After tyrosine phosphorylation by src and possibly syk protein tyrosine kinases SIT recruits the SH2 domain-containing tyrosine phosphatase SHP2 via an immunoreceptor tyrosine-based inhibition motif.@@@@1@26@@oe@16-12-2010 1020903606@GENIA Treebank@formal@@1@S@Overexpression of SIT in Jurkat cells downmodulates T cell receptor- and phytohemagglutinin-mediated activation of the nuclear factor of activated T cells (NF-AT) by interfering with signaling processes that are probably located upstream of activation of phospholipase C.@@@@1@40@@oe@16-12-2010 1020903607@GENIA Treebank@formal@@1@S@However, binding of SHP2 to SIT is not required for inhibition of NF-AT induction, suggesting that SIT not only regulates NF-AT activity but also controls NF-AT unrelated pathways of T cell activation involving SHP2.@@@@1@37@@oe@16-12-2010 1020904101@GENIA Treebank@formal@@1@S@GrpL, a Grb2-related adaptor protein, interacts with SLP-76 to regulate nuclear factor of activated T cell activation.@@@@1@20@@oe@16-12-2010 1020904102@GENIA Treebank@formal@@1@S@Propagation of signals from the T cell antigen receptor (TCR) involves a number of adaptor molecules.@@@@1@19@@oe@16-12-2010 1020904103@GENIA Treebank@formal@@1@S@SH2 domain-containing protein 76 (SLP-76) interacts with the guanine nucleotide exchange factor Vav to activate the nuclear factor of activated cells (NF-AT), and its expression is required for normal T cell development.@@@@1@38@@oe@16-12-2010 1020904104@GENIA Treebank@formal@@1@S@We report the cloning and characterization of a novel Grb2-like adaptor molecule designated as Grb2-related protein of the lymphoid system (GrpL).@@@@1@24@@oe@16-12-2010 1020904105@GENIA Treebank@formal@@1@S@Expression of GrpL is restricted to hematopoietic tissues, and it is distinguished from Grb2 by having a proline-rich region.@@@@1@21@@oe@16-12-2010 1020904106@GENIA Treebank@formal@@1@S@GrpL can be coimmunoprecipitated with SLP-76 but not with Sos1 or Sos2 from Jurkat cell lysates.@@@@1@17@@oe@16-12-2010 1020904107@GENIA Treebank@formal@@1@S@In contrast, Grb2 can be coimmunoprecipitated with Sos1 and Sos2 but not with SLP-76.@@@@1@16@@oe@16-12-2010 1020904108@GENIA Treebank@formal@@1@S@Moreover, tyrosine-phosphorylated LAT/pp36/38 in detergent lysates prepared from anti-CD3 stimulated T cells associated with Grb2 but not GrpL.@@@@1@20@@oe@16-12-2010 1020904109@GENIA Treebank@formal@@1@S@These data reveal the presence of distinct complexes involving GrpL and Grb2 in T cells.@@@@1@16@@oe@16-12-2010 1020904110@GENIA Treebank@formal@@1@S@A functional role of the GrpL-SLP-76 complex is suggested by the ability of GrpL to act alone or in concert with SLP-76 to augment NF-AT activation in Jurkat T cells.@@@@1@31@@oe@16-12-2010 1021032101@GENIA Treebank@formal@@1@S@Unexpected and coordinated expression of Spi-1, Fli-1, and megakaryocytic genes in four Epo-dependent cell lines established from transgenic mice displaying erythroid-specific expression of a thermosensitive SV40 T antigen.@@@@1@31@@oe@16-12-2010 1021032102@GENIA Treebank@formal@@1@S@Most erythroleukemic cell lines established in vitro coexpress erythrocytic and megakaryocytic markers that often are associated with expression of Spi-1 and/or Fli-1 transcription factors known as transactivators of megakaryocyte-specific promoters.@@@@1@31@@oe@16-12-2010 1021032103@GENIA Treebank@formal@@1@S@In the present study, we examined the possibility of establishing new cell lines keeping strictly erythroid-specific properties in vitro through the targeted and conditional immortalization of erythrocytic progenitors.@@@@1@30@@oe@16-12-2010 1021032104@GENIA Treebank@formal@@1@S@For that purpose, we established several lines of transgenic mice displaying erythroid-specific expression of a thermosensitive SV40 T antigen.@@@@1@21@@oe@16-12-2010 1021032105@GENIA Treebank@formal@@1@S@As expected, these transgenic mice developed splenomegaly due to the massive amplification of Ter 119 positive erythroid nucleated cells expressing T antigen.@@@@1@24@@oe@16-12-2010 1021032106@GENIA Treebank@formal@@1@S@Despite this drastic effect in vivo, the in vitro immortalization of erythropoietin-dependent erythroid progenitors unexpectedly occurred at low frequency, and all four cell lines established expressed both erythrocytic (globins) and megakaryocytic markers (glycoprotein IIb, platelet factor 4) as well as Spi-1 and Fli-1 transcripts at permissive temperature.@@@@1@55@@oe@16-12-2010 1021032107@GENIA Treebank@formal@@1@S@Switching the cells to the nonpermissive temperature led to a marked increase in globin gene expression and concomitant decrease in expression of Spi-1, Fli-1, and megakaryocytic genes in an erythropoietin-dependent manner.@@@@1@34@@oe@16-12-2010 1021032108@GENIA Treebank@formal@@1@S@Interestingly, enhanced expression of Spi-1 and Fli-1 genes already was detected in the Ter 119 positive cell population of transgenic mice spleen in vivo.@@@@1@26@@oe@16-12-2010 1021032109@GENIA Treebank@formal@@1@S@However, like normal Ter 119 erythroid cells, these Ter 119 positive cells from transgenic mice still expressed high levels of beta-globin and very low or undetectable glycoprotein IIb and platelet factor 4 megakaryocytic transcripts.@@@@1@37@@oe@16-12-2010 1021032110@GENIA Treebank@formal@@1@S@Taken together, these data indicate that the unexpected expression of megakaryocytic genes is a specific property of immortalized cells that cannot be explained only by enhanced expression of Spi-1 and/or Fli-1 genes.@@@@1@35@@oe@16-12-2010 1021032201@GENIA Treebank@formal@@1@S@Retinoic acid induces apoptosis of human CD34+ hematopoietic progenitor cells: involvement of retinoic acid receptors and retinoid X receptors depends on lineage commitment of the hematopoietic progenitor cells.@@@@1@30@@oe@16-12-2010 1021032202@GENIA Treebank@formal@@1@S@Retinoids are bifunctional regulators of growth and differentiation of hematopoietic cells.@@@@1@12@@oe@16-12-2010 1021032203@GENIA Treebank@formal@@1@S@In this study we explored the effects of retinoic acid (RA) on apoptosis of human CD34+ hematopoietic progenitor cells isolated from normal bone marrow.@@@@1@27@@oe@16-12-2010 1021032204@GENIA Treebank@formal@@1@S@RA (100 nM) induced an increase in the percentage of dead cells from 24% to 44% at day 6 (p < 0.05, n = 6) as compared to control cells cultured in medium alone.@@@@1@42@@oe@16-12-2010 1021032205@GENIA Treebank@formal@@1@S@The effect was dose dependent and appeared relatively late.@@@@1@10@@oe@16-12-2010 1021032206@GENIA Treebank@formal@@1@S@Significant differences were observed from day 4 onward.@@@@1@9@@oe@16-12-2010 1021032207@GENIA Treebank@formal@@1@S@Apoptosis, or programmed cell death, was demonstrated as the mode of cell death by using the TUNEL assay, which detects single strand nicks in DNA, or by the Nicoletti technique demonstrating a subdiploid population by DNA staining.@@@@1@42@@oe@16-12-2010 1021032208@GENIA Treebank@formal@@1@S@RA previously was found to inhibit granulocyte colony-stimulating factor--and not granulocyte-macrophage colony-stimulating factor--stimulated proliferation of CD34+ cells.@@@@1@22@@oe@16-12-2010 1021032209@GENIA Treebank@formal@@1@S@However, we found that RA opposed anti-apoptotic effects of G-CSF and GM-CSF on CD34+ cells (G-CSF: 8% dead cells at day 6; G-CSF + RA: 20%; GM-CSF: 12%; GM-CSF + RA: 27%).@@@@1@47@@oe@16-12-2010 1021032210@GENIA Treebank@formal@@1@S@Moreover, RA induced apoptosis of CD34+ cells and CD34+CD71+ cells stimulated with erythropoietin.@@@@1@15@@oe@16-12-2010 1021032211@GENIA Treebank@formal@@1@S@To explore the receptor signaling pathways involved in RA-induced apoptosis, we used selective ligands for retinoic acid receptors (RARs; RO13-7410) and retinoid X receptors (RXRs; RO 25-6603).@@@@1@35@@oe@16-12-2010 1021032212@GENIA Treebank@formal@@1@S@We found that RARs were involved in RA-mediated apoptosis of myeloid progenitor cells, whereas RARs as well as RXRs were involved in RA-mediated apoptosis of erythroid progenitor cells.@@@@1@30@@oe@16-12-2010 1021064501@GENIA Treebank@formal@@1@S@LPS-Induced NF-kappaB activation and TNF-alpha release in human monocytes are protein tyrosine kinase dependent and protein kinase C independent.@@@@1@20@@oe@16-12-2010 1021064502@GENIA Treebank@formal@@1@S@BACKGROUND: Tumor necrosis factor alpha (TNF-alpha) is an important mediator of septic shock.@@@@1@17@@oe@16-12-2010 1021064503@GENIA Treebank@formal@@1@S@Endotoxin (LPS) signal transduction in human monocytes leads to activation of nuclear factor-kappa B (NF-kappaB) and TNF-alpha release.@@@@1@23@@oe@16-12-2010 1021064504@GENIA Treebank@formal@@1@S@Previous studies have implicated activation of both protein kinase C (PKC) and protein tyrosine kinases (PTK) in LPS-induced NF-kappaB activation and TNF-alpha production.@@@@1@28@@oe@16-12-2010 1021064505@GENIA Treebank@formal@@1@S@We hypothesized that inhibition of either PKC or PTK would decrease LPS-induced NF-kappaB DNA binding and TNF-alpha release in human monocytes.@@@@1@22@@oe@16-12-2010 1021064506@GENIA Treebank@formal@@1@S@MATERIALS AND METHODS: Human monocytes were stimulated with PMA (50 ng/ml) alone or LPS (100 ng/ml) with and without a nonspecific serine/threonine protein kinase inhibitor staurosporine (Stauro), a specific pan-PKC inhibitor bisindolylmaleimide (Bis), or an inhibitor of PTK genistein (Gen).@@@@1@54@@oe@16-12-2010 1021064507@GENIA Treebank@formal@@1@S@TNF-alpha release in culture supernatants was measured by an ELISA.@@@@1@11@@oe@16-12-2010 1021064508@GENIA Treebank@formal@@1@S@NF-kappaB DNA binding was evaluated by electrophoretic mobility shift assay.@@@@1@11@@oe@16-12-2010 1021064509@GENIA Treebank@formal@@1@S@RESULTS: LPS increased NF-kappaB DNA binding and TNF-alpha release in human monocytes.@@@@1@14@@oe@16-12-2010 1021064510@GENIA Treebank@formal@@1@S@Nonspecific protein kinase inhibition inhibited NF-kappaB activation and TNF-alpha release, while specific PKC inhibition with Bis had no effect on LPS-induced NF-kappaB DNA binding or TNF-alpha release.@@@@1@29@@oe@16-12-2010 1021064511@GENIA Treebank@formal@@1@S@PTK inhibition with Gen attenuated both LPS-induced NF-kappaB DNA binding and TNF-alpha production in human monocytes.@@@@1@17@@oe@16-12-2010 1021064512@GENIA Treebank@formal@@1@S@Direct activation of PKC with PMA induced both NF-kappaB activation and TNF-alpha production by human monocytes.@@@@1@17@@oe@16-12-2010 1021064513@GENIA Treebank@formal@@1@S@CONCLUSIONS: These results suggest that LPS-induced NF-kappaB activation and TNF-alpha release in human monocytes are independent of PKC activity.@@@@1@21@@oe@16-12-2010 1021064514@GENIA Treebank@formal@@1@S@Furthermore, our results provide evidence that PTK plays a role in LPS-induced NF-kappaB activation and TNF-alpha release in human monocytes and thus could be a potential therapeutic target in inflammatory states.@@@@1@33@@oe@16-12-2010 1021064515@GENIA Treebank@formal@@1@S@Copyright 1999 Academic Press.@@@@1@5@@oe@16-12-2010 1021238901@GENIA Treebank@formal@@1@S@Dicarba-closo-dodecaboranes as a pharmacophore.@@@@1@5@@oe@16-12-2010 1021238902@GENIA Treebank@formal@@1@S@Retinoidal antagonists and potential agonists.@@@@1@6@@oe@16-12-2010 1021238903@GENIA Treebank@formal@@1@S@Synthesis and biological evaluation of the first dicarba-closo-dodecaborane (carborane) derivatives of retinoids are described.@@@@1@17@@oe@16-12-2010 1021238904@GENIA Treebank@formal@@1@S@Their retinoidal activity were examined in terms of the differentiation-inducing ability toward human promyelocytic leukemia HL-60 cells.@@@@1@18@@oe@16-12-2010 1021238905@GENIA Treebank@formal@@1@S@High retinoidal activity (agonist or antagonist for retinoic acid receptor (RAR) requires a carboxylic acid moiety and an appropriate hydrophobic group located at a suitable position on the molecule.@@@@1@33@@oe@16-12-2010 1021238906@GENIA Treebank@formal@@1@S@The 4-carboranyl-substituted compounds (7, 11) showed antagonistic activity but no agonistic activity even in the presence of the potent synergist HX630.@@@@1@25@@oe@16-12-2010 1021238907@GENIA Treebank@formal@@1@S@On the other hand, the 3-carboranyl-substituted compounds (8, 12) showed potential agonistic activity, but no antagonistic activity.@@@@1@23@@oe@16-12-2010 1021238908@GENIA Treebank@formal@@1@S@The results indicates that carboranes are applicable as the hydrophobic moiety of biologically active molecules.@@@@1@16@@oe@16-12-2010 1021485401@GENIA Treebank@formal@@1@S@Modulation of the immune response and tumor growth by activated Ras.@@@@1@12@@oe@16-12-2010 1021485402@GENIA Treebank@formal@@1@S@As a result of its transforming abilities, activated Ras is expressed in a great number of cancers.@@@@1@19@@oe@16-12-2010 1021485403@GENIA Treebank@formal@@1@S@The ras mutation frequency varies between 95% in pancreatic cancer and 5% in breast cancer.@@@@1@18@@oe@16-12-2010 1021485404@GENIA Treebank@formal@@1@S@In leukemia, the highest frequency (30%) is found in acute myeloid leukemia.@@@@1@17@@oe@16-12-2010 1021485405@GENIA Treebank@formal@@1@S@The presence of ras mutations has been correlated with a poor prognosis and negative clinical outcome.@@@@1@17@@oe@16-12-2010 1021485406@GENIA Treebank@formal@@1@S@This suggests that mutated Ras activates mechanisms, which favor tumor growth, enhance the metastatic capacity of tumors or modulate tumor-specific immune responses.@@@@1@25@@oe@16-12-2010 1021485407@GENIA Treebank@formal@@1@S@Several new functions of Ras, such as downregulation of major histocompatibility complex molecules, upregulation of certain cytokines, growth factors and degradative enzymes have been uncovered in the last decade.@@@@1@33@@oe@16-12-2010 1021485408@GENIA Treebank@formal@@1@S@Additionally, mutated Ras can also serve as a primary target for the development of immunotherapy or drug therapy.@@@@1@20@@oe@16-12-2010 1021485409@GENIA Treebank@formal@@1@S@This review will discuss the mechanisms by which Ras expressing tumors are able to evade destruction by the immune system and enhance their growth and metastatic potential.@@@@1@28@@oe@16-12-2010 1021485410@GENIA Treebank@formal@@1@S@It will further elaborate on the attempts to develop successful immunotherapy and drug therapy targeting Ras expressing tumors.@@@@1@19@@oe@16-12-2010 1021607101@GENIA Treebank@formal@@1@S@Expression of E2A-HLF chimeric protein induced T-cell apoptosis, B-cell maturation arrest, and development of acute lymphoblastic leukemia.@@@@1@20@@oe@16-12-2010 1021607102@GENIA Treebank@formal@@1@S@The E2A-HLF fusion gene, generated by t(17;19)(q22;p13) in acute lymphoblastic leukemia (ALL), encodes a chimeric transcription factor in which the trans-activating domains of E2A are fused to the DNA- binding and dimerization domains of hepatic leukemic factor (HLF).@@@@1@44@@oe@16-12-2010 1021607103@GENIA Treebank@formal@@1@S@To investigate its biological role, we generated transgenic mice expressing E2A-HLF using Ig enhancer and promoter, which direct transgene expression in cells committed to the lymphoid lineage.@@@@1@30@@oe@16-12-2010 1021607104@GENIA Treebank@formal@@1@S@The transgenic mice exhibited abnormal development in the thymus and spleen and were susceptible to infection.@@@@1@17@@oe@16-12-2010 1021607105@GENIA Treebank@formal@@1@S@The thymus contained small numbers of thymocytes, and TUNEL staining showed that higher population of thymocytes were undergoing apoptosis.@@@@1@21@@oe@16-12-2010 1021607106@GENIA Treebank@formal@@1@S@The spleen exhibited a marked reduction in splenic lymphocytes and the flow cytometric analyses and the in vitro colony formation assays showed that the B-cell maturation was blocked at a very early developmental stage.@@@@1@35@@oe@16-12-2010 1021607107@GENIA Treebank@formal@@1@S@These findings indicated that the expression of E2A-HLF induced T-cell apoptosis and B-cell maturation arrest in vivo and that the susceptibility of the transgenic mice to infection was due to immunodeficiency.@@@@1@32@@oe@16-12-2010 1021607108@GENIA Treebank@formal@@1@S@Moreover, several transgenic mice developed acute leukemia, classified as T-ALL based on the surface marker analysis and DNA rearrangements, suggesting that an additional event is required for malignant transformation of lymphoid cells expressing E2A-HLF.@@@@1@38@@oe@16-12-2010 1021607109@GENIA Treebank@formal@@1@S@Our findings provide insight into the biological function of E2A-HLF in lymphoid development and also its role in leukemogenesis.@@@@1@20@@oe@16-12-2010 1021753401@GENIA Treebank@formal@@1@S@Cellular disposition of sulphamethoxazole and its metabolites: implications for hypersensitivity.@@@@1@12@@oe@16-12-2010 1021753402@GENIA Treebank@formal@@1@S@1. Bioactivation of sulphamethoxazole (SMX) to chemically-reactive metabolites and subsequent protein conjugation is thought to be involved in SMX hypersensitivity.@@@@1@23@@oe@16-12-2010 1021753403@GENIA Treebank@formal@@1@S@We have therefore examined the cellular metabolism, disposition and conjugation of SMX and its metabolites in vitro.@@@@1@19@@oe@16-12-2010 1021753404@GENIA Treebank@formal@@1@S@2. Flow cytometry revealed binding of N-hydroxy (SMX-NHOH) and nitroso (SMX-NO) metabolites of SMX, but not of SMX itself, to the surface of viable white blood cells.@@@@1@34@@oe@16-12-2010 1021753405@GENIA Treebank@formal@@1@S@Cellular haptenation by SMX-NO was reduced by exogenous glutathione (GSH).@@@@1@13@@oe@16-12-2010 1021753406@GENIA Treebank@formal@@1@S@3. SMX-NHOH and SMX-NO were rapidly reduced back to the parent compound by cysteine (CYS), GSH, human peripheral blood cells and plasma, suggesting that this is an important and ubiquitous bioinactivation mechanism.@@@@1@38@@oe@16-12-2010 1021753407@GENIA Treebank@formal@@1@S@4. Fluorescence HPLC showed that SMX-NHOH and SMX-NO depleted CYS and GSH in buffer, and to a lesser extent, in cells and plasma.@@@@1@26@@oe@16-12-2010 1021753408@GENIA Treebank@formal@@1@S@5. Neutrophil apoptosis and inhibition of neutrophil function were induced at lower concentrations of SMX-NHOH and SMX-NO than those inducing loss of membrane viability, with SMX having no effect.@@@@1@31@@oe@16-12-2010 1021753409@GENIA Treebank@formal@@1@S@Lymphocytes were significantly (P<0.05) more sensitive to the direct cytotoxic effects of SMX-NO than neutrophils.@@@@1@20@@oe@16-12-2010 1021753410@GENIA Treebank@formal@@1@S@6. Partitioning of SMX-NHOH into red blood cells was significantly (P<0.05) lower than with the hydroxylamine of dapsone.@@@@1@23@@oe@16-12-2010 1021753411@GENIA Treebank@formal@@1@S@7. Our results suggest that the balance between oxidation of SMX to its toxic metabolites and their reduction is an important protective cellular mechanism.@@@@1@25@@oe@16-12-2010 1021753412@GENIA Treebank@formal@@1@S@If an imbalance exists, haptenation of the toxic metabolites to bodily proteins including the surface of viable cells can occur, and may result in drug hypersensitivity.@@@@1@29@@oe@16-12-2010 1022125001@GENIA Treebank@formal@@1@S@Leukocyte populations, hormone receptors and apoptosis in eutopic and ectopic first trimester human pregnancies.@@@@1@16@@oe@16-12-2010 1022125002@GENIA Treebank@formal@@1@S@The implantation of trophoblast cells at extrauterine sites still results in decidualization.@@@@1@13@@oe@16-12-2010 1022125003@GENIA Treebank@formal@@1@S@The objective of the present study was to compare decidualization at eutopic and ectopic implantation sites.@@@@1@17@@oe@16-12-2010 1022125004@GENIA Treebank@formal@@1@S@Tissues from women undergoing elective termination of uterine pregnancy and from women with ectopic pregnancy were used to detect the presence of cells important for the maintenance of pregnancy, such as BCL-2+, CD56+, CD3+, CD8+ and CD68+ cells, and the presence of oestrogen (ER) and progesterone receptors (PR) by immunohistochemistry.@@@@1@60@@oe@16-12-2010 1022125005@GENIA Treebank@formal@@1@S@In-situ detection of fragmented DNA was performed to identify apoptotic cells.@@@@1@12@@oe@16-12-2010 1022125006@GENIA Treebank@formal@@1@S@The percentage of CD3+ cells among all immunocompetent cells in the tubal epithelium was 46.6% (39.9% of CD3+ were also CD8+); the other 53.4% were CD68+ cells.@@@@1@34@@oe@16-12-2010 1022125007@GENIA Treebank@formal@@1@S@CD56+ cells were undetectable in ectopic decidua at the feto-maternal interface in ectopic tissue.@@@@1@15@@oe@16-12-2010 1022125008@GENIA Treebank@formal@@1@S@In uterine decidua, we found 29.9% CD3+ cells (2.2% of CD3+ were CD8+), 51.6% CD56+ cells and 18.5% CD68+ cells.@@@@1@29@@oe@16-12-2010 1022125009@GENIA Treebank@formal@@1@S@The ratio of BCL2+ to CD3+ cells in ectopic pregnancy was 0.41.@@@@1@13@@oe@16-12-2010 1022125010@GENIA Treebank@formal@@1@S@In uterine pregnancy, the ratio of BCL-2 to CD3 was 0.44 and 0.39 for CD56.@@@@1@17@@oe@16-12-2010 1022125011@GENIA Treebank@formal@@1@S@Tissues from both ectopic and uterine pregnancies were positive for PR.@@@@1@12@@oe@16-12-2010 1022125012@GENIA Treebank@formal@@1@S@Fewer apoptotic cell bodies were present in ectopic pregnancy.@@@@1@10@@oe@16-12-2010 1022125013@GENIA Treebank@formal@@1@S@The use of tissue obtained from ectopic pregnancy may become an excellent model to identify the mechanism of trophoblast invasion in eutopic pregnancies.@@@@1@24@@oe@16-12-2010 1022164301@GENIA Treebank@formal@@1@S@Tcf-1-mediated transcription in T lymphocytes: differential role for glycogen synthase kinase-3 in fibroblasts and T cells.@@@@1@18@@oe@16-12-2010 1022164302@GENIA Treebank@formal@@1@S@Beta-catenin is the vertebrate homolog of the Drosophila segment polarity gene Armadillo and plays roles in both cell-cell adhesion and transduction of the Wnt signaling cascade.@@@@1@27@@oe@16-12-2010 1022164303@GENIA Treebank@formal@@1@S@Recently, members of the Lef/Tcf transcription factor family have been identified as protein partners of beta-catenin, explaining how beta-catenin alters gene expression.@@@@1@25@@oe@16-12-2010 1022164304@GENIA Treebank@formal@@1@S@Here we report that in T cells, Tcf-1 also becomes transcriptionally active through interaction with beta-catenin, suggesting that the Wnt signal transduction pathway is operational in T lymphocytes as well.@@@@1@33@@oe@16-12-2010 1022164305@GENIA Treebank@formal@@1@S@However, although Wnt signals are known to inhibit the activity of the negative regulatory protein kinase glycogen synthase kinase-3beta (GSK-3beta), resulting in increased levels of beta-catenin, we find no evidence for involvement of GSK-3beta in Tcf-mediated transcription in T cells.@@@@1@46@@oe@16-12-2010 1022164306@GENIA Treebank@formal@@1@S@That is, a dominant negative GSK-3beta does not specifically activate Tcf transcription and stimuli (lithium or phytohemagglutinin) that inhibit GSK-3beta activity also do not activate Tcf reporter genes.@@@@1@32@@oe@16-12-2010 1022164307@GENIA Treebank@formal@@1@S@Thus, inhibition of GSK-3beta is insufficient to activate Tcf-dependent transcription in T lymphocytes.@@@@1@15@@oe@16-12-2010 1022164308@GENIA Treebank@formal@@1@S@In contrast, in C57MG fibroblast cells, lithium inactivates GSK-3beta and induces Tcf-controlled transcription.@@@@1@16@@oe@16-12-2010 1022164309@GENIA Treebank@formal@@1@S@This is the first demonstration that lithium can alter gene expression of Tcf-responsive genes, and points to a difference in regulation of Wnt signaling between fibroblasts and lymphocytes.@@@@1@30@@oe@16-12-2010 1022165801@GENIA Treebank@formal@@1@S@CIITA-induced occupation of MHC class II promoters is independent of the cooperative stabilization of the promoter-bound multi-protein complexes.@@@@1@19@@oe@16-12-2010 1022165802@GENIA Treebank@formal@@1@S@Precise regulation of MHC class II expression plays a crucial role in the control of the immune response.@@@@1@19@@oe@16-12-2010 1022165803@GENIA Treebank@formal@@1@S@The transactivator CIITA behaves as a master controller of constitutive and inducible MHC class II gene activation, but its exact mechanism of action is not known.@@@@1@28@@oe@16-12-2010 1022165804@GENIA Treebank@formal@@1@S@Activation of MHC class II promoters requires binding of at least three distinct multi-protein complexes (RFX, X2BP and NF-Y).@@@@1@23@@oe@16-12-2010 1022165805@GENIA Treebank@formal@@1@S@It is known that the stability of this binding results from cooperative interactions between these proteins.@@@@1@17@@oe@16-12-2010 1022165806@GENIA Treebank@formal@@1@S@We show here that expression of CIITA in MHC class II- cells triggers occupation of the promoters by these complexes.@@@@1@20@@oe@16-12-2010 1022165807@GENIA Treebank@formal@@1@S@This observation raised the possibility that the effect of CIITA on promoter occupation is mediated by an effect on the cooperative stabilization of the DNA-bound multi-protein complexes.@@@@1@28@@oe@16-12-2010 1022165808@GENIA Treebank@formal@@1@S@We show, however, that the presence of CIITA does not affect the stability of the higher-order protein complex formed on DNA by RFX, X2BP and NF-Y.@@@@1@30@@oe@16-12-2010 1022165809@GENIA Treebank@formal@@1@S@This suggests other mechanisms for CIITA-induced promoter occupancy, such as an effect on chromatin structure leading to increased accessibility of MHC class II promoters.@@@@1@26@@oe@16-12-2010 1022165810@GENIA Treebank@formal@@1@S@This ability of CIITA to facilitate promoter occupation is undissociable from its transactivation potential.@@@@1@15@@oe@16-12-2010 1022165811@GENIA Treebank@formal@@1@S@Finally, we conclude that this effect of CIITA is cell-type specific, since expression of CIITA is not required for normal occupation of MHC class II promoters in B lymphocytes.@@@@1@32@@oe@16-12-2010 1022410901@GENIA Treebank@formal@@1@S@Immunosuppressant PG490 (triptolide) inhibits T-cell interleukin-2 expression at the level of purine-box/nuclear factor of activated T-cells and NF-kappaB transcriptional activation.@@@@1@23@@oe@16-12-2010 1022410902@GENIA Treebank@formal@@1@S@PG490 (triptolide) is a diterpene triepoxide with potent immunosuppressive and antiinflammatory properties.@@@@1@15@@oe@16-12-2010 1022410903@GENIA Treebank@formal@@1@S@PG490 inhibits interleukin(IL)-2 expression by normal human peripheral blood lymphocytes stimulated with phorbol 12-myristate 13-acetate (PMA) and antibody to CD3 (IC50 of 10 ng/ml), and with PMA and ionomycin (Iono, IC50 of 40 ng/ml).@@@@1@47@@oe@16-12-2010 1022410904@GENIA Treebank@formal@@1@S@In Jurkat T-cells, PG490 inhibits PMA/Iono-stimulated IL-2 transcription.@@@@1@10@@oe@16-12-2010 1022410905@GENIA Treebank@formal@@1@S@PG490 inhibits the induction of DNA binding activity at the purine-box/antigen receptor response element (ARRE)/nuclear factor of activated T-cells (NF-AT) target sequence but not at the NF-kappaB site.@@@@1@37@@oe@16-12-2010 1022410906@GENIA Treebank@formal@@1@S@PG490 can completely inhibit transcriptional activation at the purine-box/ARRE/NF-AT and NF-kappaB target DNA sequences triggered by all stimuli examined (PMA, PMA/Iono, tumor necrosis factor-alpha).@@@@1@29@@oe@16-12-2010 1022410907@GENIA Treebank@formal@@1@S@PG490 also inhibits PMA-stimulated activation of a chimeric transcription factor in which the C-terminal TA1 transactivation domain of NF-kappaB p65 is fused to the DNA binding domain of GAL4.@@@@1@30@@oe@16-12-2010 1022410908@GENIA Treebank@formal@@1@S@In 16HBE human bronchial epithelial cells, IL-8 expression is regulated predominantly by NF-kappaB, and PG490 but not cyclosporin A can completely inhibit expression of IL-8.@@@@1@28@@oe@16-12-2010 1022410909@GENIA Treebank@formal@@1@S@The mechanism of PG490 inhibition of cytokine gene expression differs from cyclosporin A and involves nuclear inhibition of transcriptional activation of NF-kappaB and the purine-box regulator operating at the ARRE/NF-AT site at a step after specific DNA binding.@@@@1@39@@oe@16-12-2010 1022413501@GENIA Treebank@formal@@1@S@Differential inhibition of Smad6 and Smad7 on bone morphogenetic protein- and activin-mediated growth arrest and apoptosis in B cells.@@@@1@20@@oe@16-12-2010 1022413502@GENIA Treebank@formal@@1@S@Smad6 and Smad7 prevent ligand-induced activation of signal-transducing Smad proteins in the transforming growth factor-beta family.@@@@1@17@@oe@16-12-2010 1022413503@GENIA Treebank@formal@@1@S@Here we demonstrate that both Smad6 and Smad7 are human bone morphogenetic protein-2 (hBMP-2)-inducible antagonists of hBMP-2-induced growth arrest and apoptosis in mouse B cell hybridoma HS-72 cells.@@@@1@32@@oe@16-12-2010 1022413504@GENIA Treebank@formal@@1@S@Moreover, we confirmed that the ectopic expressions of Smad6 and Smad7 inhibited the hBMP-2-induced Smad1/Smad5 phosphorylation.@@@@1@18@@oe@16-12-2010 1022413505@GENIA Treebank@formal@@1@S@We previously reported that Smad7 is an activin A-inducible antagonist of activin A-induced growth arrest and apoptosis in HS-72 cells.@@@@1@21@@oe@16-12-2010 1022413506@GENIA Treebank@formal@@1@S@Interestingly, although mRNA expression of Smad6 was induced by activin A in HS-72 cells, Smad6 showed no antagonistic effect on activin A-induced growth arrest and apoptosis.@@@@1@29@@oe@16-12-2010 1022413507@GENIA Treebank@formal@@1@S@Moreover, we found that the ectopic expression of Smad7, but not Smad6, inhibited the activin A-induced Smad2 phosphorylation in HS-72 cells.@@@@1@25@@oe@16-12-2010 1022413508@GENIA Treebank@formal@@1@S@Thus, Smad6 and Smad7 exhibit differential inhibitory effects in bone morphogenetic protein-2- and activin A-mediated signaling in B lineage cells.@@@@1@22@@oe@16-12-2010 1022415601@GENIA Treebank@formal@@1@S@Transcription factors Sp1 and AP-2 mediate induction of acid sphingomyelinase during monocytic differentiation.@@@@1@14@@oe@16-12-2010 1022415602@GENIA Treebank@formal@@1@S@Cells from the human monocytic leukemia cell line THP-1 differentiate towards a macrophage-like phenotype when stimulated with phorbol 12-myristate -13- acetate (PMA), 1,25-dihydroxy-vitamin D3, and various other agents.@@@@1@31@@oe@16-12-2010 1022415603@GENIA Treebank@formal@@1@S@We demonstrate here that the expression of the lysosomal enzyme acid sphingomyelinase (ASM; E.C.3.1.4.12) is induced during this process and is strongly elevated in differentiated THP-1 cells, as well as in differentiated human mononuclear phagocytes.@@@@1@40@@oe@16-12-2010 1022415604@GENIA Treebank@formal@@1@S@Using Northern blotting, RNase protection assay, and nuclear run-on analyses, we show that the up-regulation of ASM expression is regulated mainly at the level of transcription and that new protein synthesis is required for enhanced ASM activity.@@@@1@41@@oe@16-12-2010 1022415605@GENIA Treebank@formal@@1@S@This cell-type specific induction by PMA treatment was further investigated with respect to transcriptional control.@@@@1@16@@oe@16-12-2010 1022415606@GENIA Treebank@formal@@1@S@A series of 5' deletion derivatives of the upstream regulatory region were used in transient transfection assays to identify promoter elements required for basal and inducible gene expression.@@@@1@29@@oe@16-12-2010 1022415607@GENIA Treebank@formal@@1@S@A PMA responsive element was localized to a region between -319 and -219 bp upstream of the initiation codon and co-transfections with transcription factor expression plasmids for AP-2 and Sp1 resulted in augmented ASM promoter activity, which was abolished when the binding sites for these two factors were deleted.@@@@1@51@@oe@16-12-2010 1022415608@GENIA Treebank@formal@@1@S@Using electrophoretic mobility shift assays and supershift assays we demonstrate that this region is specifically bound by Sp1 and AP-2.@@@@1@21@@oe@16-12-2010 1022415609@GENIA Treebank@formal@@1@S@These factors are present in nuclear extracts prepared from both induced and uninduced THP-1 cells.@@@@1@16@@oe@16-12-2010 1022415610@GENIA Treebank@formal@@1@S@However, the intensity of the complex formed appeared to increase when nuclear extracts from PMA-treated cells were used.@@@@1@20@@oe@16-12-2010 1022415611@GENIA Treebank@formal@@1@S@From these studies, we conclude that a concerted action of the transcription factors AP-2 and Sp1 is essential for the up -regulation of ASM expression during the process of macrophage differentiation.@@@@1@32@@oe@16-12-2010 1022422301@GENIA Treebank@formal@@1@S@Estrogen and progesterone induction of survival of monoblastoid cells undergoing TNF-alpha-induced apoptosis.@@@@1@13@@oe@16-12-2010 1022422302@GENIA Treebank@formal@@1@S@Induction of apoptosis of mononucleated cells is a physiological process for regulating the intensity of the immune response.@@@@1@19@@oe@16-12-2010 1022422303@GENIA Treebank@formal@@1@S@The female steroid hormones estrogen (E2) and progesterone (Prog) are known to modulate the reactivity of the immune system; recently it has been demonstrated that they can regulate induction of apoptosis of endothelial cells and osteoblasts.@@@@1@42@@oe@16-12-2010 1022422304@GENIA Treebank@formal@@1@S@TNF-alpha-mediated induction of apoptosis has been well characterized in myeloid cells.@@@@1@12@@oe@16-12-2010 1022422305@GENIA Treebank@formal@@1@S@We investigated whether E2 and Prog could interfere with TNF-alpha-induced apoptosis of the monoblastoid U937 cell line.@@@@1@18@@oe@16-12-2010 1022422306@GENIA Treebank@formal@@1@S@Treatment with E2 or Prog increased survival and prevented apoptosis induced by TNF-alpha in both undifferentiated and macrophage-like PMA-differentiated U937 cells, as assessed by trypan blue exclusion cell counting, thymidine incorporation, AnnexinV labeling, followed by flow cytometry and DNA fragmentation studies.@@@@1@46@@oe@16-12-2010 1022422307@GENIA Treebank@formal@@1@S@This effect can be associated with the activation of specific hormone receptors, since we observed the expression of the estrogen receptor alpha (ER-alpha), ER-beta, and progesterone receptor (PR) mRNAs; the ER-alpha protein expression was confirmed by immunocytochemical analysis.@@@@1@47@@oe@16-12-2010 1022422308@GENIA Treebank@formal@@1@S@In addition, hormone-mediated survival against apoptosis was concentration dependent, reaching the half-maximal effect at 10 nM and blocked by the ER antagonist ICI 182,780 in undifferentiated cells, further supporting a receptor-mediated mechanism of cell survival.@@@@1@41@@oe@16-12-2010 1022422309@GENIA Treebank@formal@@1@S@Other steroid receptor drugs such as Raloxifene, RU486, or the ICI 182,780 in PMA-differentiated cells displayed agonist activity by preventing TNF-alpha-induced apoptosis as efficiently as the hormones alone, providing further evidence to the notion that steroid receptor drugs may manifest agonist or antagonist activities depending on the cellular context in which they are studied.@@@@1@60@@oe@16-12-2010 1022422310@GENIA Treebank@formal@@1@S@Treatment with E2 was also associated with a time-dependent decrease in the mRNA level of the proapoptotic Nip-2 protein, supporting the hypothesis that hormone responsiveness of U937 cells is mediated by target gene transcription.@@@@1@36@@oe@16-12-2010 1022422311@GENIA Treebank@formal@@1@S@Together, these results demonstrate that ER and PR can be activated by endogenous or exogenous ligands to induce a genetic response that impairs TNF-alpha-induced apoptosis in U937 cells.@@@@1@30@@oe@16-12-2010 1022422312@GENIA Treebank@formal@@1@S@The data presented here suggest that the female steroid receptors play a role in regulation of the immune response by preventing apoptosis of monoblastoid cells; this effect might have important consequences in the clinical use of steroid receptor drugs.@@@@1@41@@oe@16-12-2010 1022422313@GENIA Treebank@formal@@1@S@--Vegeto, E., Pollio, G., Pellicciari, C., Maggi, A.@@@@1@17@@oe@16-12-2010 1022422314@GENIA Treebank@formal@@1@S@Estrogen and progesterone induction of survival of monoblastoid cells undergoing TNF-alpha-inuced apoptosis.@@@@1@13@@oe@16-12-2010 1022427801@GENIA Treebank@formal@@1@S@Grf40, A novel Grb2 family member, is involved in T cell signaling through interaction with SLP-76 and LAT.@@@@1@21@@oe@16-12-2010 1022427802@GENIA Treebank@formal@@1@S@We molecularly cloned a new Grb2 family member, named Grf40, containing the common SH3-SH2-SH3 motif.@@@@1@18@@oe@16-12-2010 1022427803@GENIA Treebank@formal@@1@S@Expression of Grf40 is predominant in hematopoietic cells, particularly T cells.@@@@1@13@@oe@16-12-2010 1022427804@GENIA Treebank@formal@@1@S@Grf40 binds to the SH2 domain-containing leukocyte protein of 76 kD (SLP-76) via its SH3 domain more tightly than Grb2.@@@@1@23@@oe@16-12-2010 1022427805@GENIA Treebank@formal@@1@S@Incidentally, Grf40 binds to linker for activation of T cells (LAT) possibly via its SH2 domain.@@@@1@20@@oe@16-12-2010 1022427806@GENIA Treebank@formal@@1@S@Overexpression of wild-type Grf40 in Jurkat cells induced a significant increase of SLP-76-dependent interleukin (IL)-2 promoter and nuclear factor of activated T cell (NF-AT) activation upon T cell receptor (TCR) stimulation, whereas the COOH-terminal SH3-deleted Grf40 mutant lacked any recognizable increase in IL-2 promoter activity.@@@@1@54@@oe@16-12-2010 1022427807@GENIA Treebank@formal@@1@S@Furthermore, the SH2-deleted Grf40 mutant led to a marked inhibition of these regulatory activities, the effect of which is apparently stronger than that of the SH2-deleted Grb2 mutant.@@@@1@31@@oe@16-12-2010 1022427808@GENIA Treebank@formal@@1@S@Our data suggest that Grf40 is an adaptor molecule involved in TCR-mediated signaling through a more efficient interaction than Grb2 with SLP-76 and LAT.@@@@1@25@@oe@16-12-2010 1022447001@GENIA Treebank@formal@@1@S@Signal transduction through interferon-gamma receptor on human eosinophils.@@@@1@9@@oe@16-12-2010 1022447002@GENIA Treebank@formal@@1@S@BACKGROUND: We reported on the constitutive interferon-gamma receptor (IFN-gammaR) expression on eosinophils.@@@@1@16@@oe@16-12-2010 1022447003@GENIA Treebank@formal@@1@S@But signal transduction through IFN-gammaR on eosinophils remains to be elucidated.@@@@1@12@@oe@16-12-2010 1022447004@GENIA Treebank@formal@@1@S@In this study, we examined the involvement of the Jak/Stat pathway in the signaling of eosinophils after IFN-gammaR conjugation by the ligand binding.@@@@1@25@@oe@16-12-2010 1022447005@GENIA Treebank@formal@@1@S@METHODS: Purified peripheral eosinophils were stimulated with IFN-gamma at 37 degrees C for 1-60 min.@@@@1@17@@oe@16-12-2010 1022447006@GENIA Treebank@formal@@1@S@Tyrosine phosphorylation of IFN-gammaR, Jak1, Jak2, and Stat1alpha was examined by immunoblotting.@@@@1@16@@oe@16-12-2010 1022447007@GENIA Treebank@formal@@1@S@Gel-shift assay was also examined to show the formation of Stat1alpha-DNA complexes.@@@@1@13@@oe@16-12-2010 1022447008@GENIA Treebank@formal@@1@S@RESULTS: We show that binding of IFN-gamma to human eosinophils initiated a series of events that resulted in the rapid tyrosine phosphorylation of not only the IFN-gammaRalpha chain but also Jak1, Jak2, and Stat1alpha.@@@@1@38@@oe@16-12-2010 1022447009@GENIA Treebank@formal@@1@S@In addition, IFN-gamma enhanced the DNA-binding activity of Stat1alpha.@@@@1@11@@oe@16-12-2010 1022447010@GENIA Treebank@formal@@1@S@CONCLUSION: These data indicate that IFN-gamma affects eosinophils through its specific receptor and utilizes the Jak/Stat pathway as its mode of signaling.@@@@1@24@@oe@16-12-2010 1022537701@GENIA Treebank@formal@@1@S@Activation of nuclear factor-kappaB by lipopolysaccharide in mononuclear leukocytes is prevented by inhibitors of cytosolic phospholipase A2.@@@@1@18@@oe@16-12-2010 1022537702@GENIA Treebank@formal@@1@S@In monocytes, lipopolysaccharide induces synthesis and activity of the 85-kDa cytosolic phospholipase A2.@@@@1@15@@oe@16-12-2010 1022537703@GENIA Treebank@formal@@1@S@This enzyme releases arachidonic acid and lyso-phospholipids from membranes which are metabolized to eicosanoids and platelet-activating-factor.@@@@1@17@@oe@16-12-2010 1022537704@GENIA Treebank@formal@@1@S@These lipid mediators increase activity of transcription factors and expression of cytokine genes indicating a function for cytosolic phospholipase A2 in signal transduction and inflammation.@@@@1@26@@oe@16-12-2010 1022537705@GENIA Treebank@formal@@1@S@We have shown previously that trifluoromethylketone inhibitors of cytosolic phospholipase A2 suppressed interleukin-1beta protein and steady-state mRNA levels in human lipopolysaccharide-stimulated peripheral blood mononuclear leukocytes.@@@@1@26@@oe@16-12-2010 1022537706@GENIA Treebank@formal@@1@S@In this study, the subcellular mechanisms were analyzed by which trifluoromethylketones interfere with gene expression.@@@@1@17@@oe@16-12-2010 1022537707@GENIA Treebank@formal@@1@S@We found that they reduced the initial interleukin-1beta mRNA transcription rate through prevention of degradation of inhibitor-kappaB alpha.@@@@1@19@@oe@16-12-2010 1022537708@GENIA Treebank@formal@@1@S@Consequently, cytosolic activation, nuclear translocation and DNA-binding of nuclear factor-kappaB were decreased.@@@@1@15@@oe@16-12-2010 1022537709@GENIA Treebank@formal@@1@S@Trifluoromethylketones ameliorate chronic inflammation in vivo.@@@@1@7@@oe@16-12-2010 1022537710@GENIA Treebank@formal@@1@S@Thus, this therapeutic potency may reside in retention of inactive nuclear factor-kappaB in the cytosol thereby abrogating interleukin-1beta gene transcription.@@@@1@22@@oe@16-12-2010 1022597901@GENIA Treebank@formal@@1@S@Constitutive activation of an epithelial signal transducer and activator of transcription (STAT) pathway in asthma.@@@@1@18@@oe@16-12-2010 1022597902@GENIA Treebank@formal@@1@S@Cytokine effects on immunity and inflammation often depend on the transcription factors termed signal transducers and activators of transcription (STATs), so STAT signaling pathways are candidates for influencing inflammatory disease.@@@@1@34@@oe@16-12-2010 1022597903@GENIA Treebank@formal@@1@S@We reasoned that selective IFN responsiveness of the first STAT family member (Stat1) and Stat1-dependent immune-response genes such as intercellular adhesion molecule-1 (ICAM-1), IFN regulatory factor-1 (IRF-1), and Stat1 itself in airway epithelial cells provides a basis for detecting cytokine signaling abnormalities in inflammatory airway disease.@@@@1@55@@oe@16-12-2010 1022597904@GENIA Treebank@formal@@1@S@On the basis of nuclear localization and phosphorylation, we found that epithelial Stat1 (but not other control transcription factors) was invariably activated in asthmatic compared with normal control or chronic bronchitis subjects.@@@@1@36@@oe@16-12-2010 1022597905@GENIA Treebank@formal@@1@S@Furthermore, epithelial levels of activated Stat1 correlated with levels of expression for epithelial ICAM-1, IRF-1, and Stat1, and in turn, ICAM-1 levels correlated with T-cell accumulation in tissue.@@@@1@34@@oe@16-12-2010 1022597906@GENIA Treebank@formal@@1@S@However, only low levels of IFN-gamma or IFN-gamma-producing cells were detected in airway tissue in all subjects.@@@@1@19@@oe@16-12-2010 1022597907@GENIA Treebank@formal@@1@S@The results therefore provide initial evidence linking abnormal behavior of STAT pathways for cytokine signaling to the development of an inflammatory disease.@@@@1@23@@oe@16-12-2010 1022597908@GENIA Treebank@formal@@1@S@In that context, the results also change the current scheme for asthma pathogenesis to one that must include a localized gain in transcriptional signal ordinarily used for a T helper 1-type cytokine (IFN-gamma) in combination with allergy-driven overproduction of T helper 2-type cytokines.@@@@1@47@@oe@16-12-2010