Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteins belonging to the NFAT (nuclear factor of activated T cells) family of transcription factors are expressed in most immune cell types, and play a central role in the transcription of cytokine genes, such as IL-2, IL-4, IL-5, IL-13, IFN-gamma, TNF-alpha, and GM-CSF. The activity NFAT proteins is regulated by the calcium/calmodulin-dependent phosphatase calcineurin, a target for inhibition by CsA and FK506. Recently, two different groups have described that mice lacking the NFAT1 transcription factor show an enhanced immune response, with tendency towards the development of a late Th2-like response. This review evaluates the possible role of NFAT proteins in the Th2 immune response and in the eosinophil-mediated allergic response.
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PMID:Role of the cyclosporin-sensitive transcription factor NFAT1 in the allergic response. 969 27

The murine TS1alphabeta T cell line expresses the anti-apoptotic protein Bcl-2 upon IL-2 stimulation, whereas IL-4-mediated growth of this cell line proceeds in the absence of Bcl-2 expression. In addition, IL-4 stimulation inhibits Bcl-2 expression and modulates its mRNA level. IL-2-induced DNA binding activity for these transcription factors is sensitive to phosphatidylinositol 3 kinase inhibitor wortmannin and to Rho inhibitor Clostridium difficile toxin B, which inhibit IL-2-induced Bcl-2 expression. NF-AT transcription factor appears to be the most important in the control Bcl-2 expression, since inhibition of the calcium-calmodulin-dependent phosphatase calcineurin, which regulates NF-AT activity, downregulates Bcl-2 expression in IL-2-stimulated cells. Constitutive expression of this phosphatase also upregulates Bcl-2 expression in IL-4-stimulated cells. In addition, a dominant negative NF-AT expression vector downregulates Bcl-2 expression in IL-2-stimulated cells. These results suggest that IL-2 induction of Bcl-2 expression may be directly or indirectly mediated by NF-AT.
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PMID:The Bcl-2 gene is differentially regulated by IL-2 and IL-4: role of the transcription factor NF-AT. 977 66

Translation is regulated predominantly by an interplay between cis elements at the 3' and 5' ends of mRNAs and trans-acting proteins. Cyclosporin A (CsA), a calcineurin antagonist and blocker of interleukin-2 (IL-2) transcription in T cells, was found to inhibit translation of IL-3 mRNA in autocrine mast cell tumor lines. The mechanism involved ribosome-associated poly(A) shortening and required an intact AU-rich element in the 3' untranslated region. FK506, another calcineurin inhibitor, shared the effect. The translational inhibition by CsA was specific to oncogenically induced lymphokines IL-3 and IL-4 but not to IL-6, c-jun, and c-myc, which are expressed in the nonmalignant precursor cells. Furthermore, no translational down-regulation of the mRNA was observed in IL-3-transfected precursor cells. These data suggest that translational silencing is associated with the tumor phenotype.
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PMID:Cyclosporin A promotes translational silencing of autocrine interleukin-3 via ribosome-associated deadenylation. 985 12

Aggregation of high affinity FcR for IgE (Fc epsilon RI) on mast cells activates intracellular signal transduction pathways, including the activation of protein tyrosine kinases, phosphatidylinositol 3-kinase (PI3-kinase), and protein kinase C. Binding of stem cell factor (SCF) to its receptor (SCFR, c-Kit) on mast cells also induces increases in intrinsic tyrosine kinase activity and activation of PI3-kinase. Although ligation of both receptors induces Ras and Raf-1 activation, the downstream consequences of these early activation events are not well defined, except for the activation of extracellular signal-regulated kinases (ERK). Addition of Ag (OVA) to mouse bone marrow-derived mast cells (BMMC) sensitized with anti-OVA IgE triggers the activation of three members of the mitogen-activated protein (MAP) kinase family, c-Jun amino-terminal kinase (JNK), p38 MAP kinase (p38), and extracellular signal-regulated kinases. SCF similarly activates all three MAP kinases. Wortmannin, an inhibitor of PI3-kinase, inhibited both Fc epsilon RI- and SCFR-mediated JNK activation and partially inhibited Fc epsilon RI, but not SCFR-mediated p38 activation. Cyclosporin A inhibited Fc epsilon RI-mediated JNK and p38 activation, but did not affect the activation of these kinases when stimulated through the SCFR. Wortmannin and cyclosporin A inhibited Fc epsilon RI-mediated production of TNF-alpha and IL-4 in addition to serotonin release in BMMC. These results indicate that both PI3-kinase and calcineurin may contribute to the regulation of cytokine gene transcription and the degranulation response by modulating JNK activity in BMMC.
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PMID:Mitogen-activated protein kinase activation through Fc epsilon receptor I and stem cell factor receptor is differentially regulated by phosphatidylinositol 3-kinase and calcineurin in mouse bone marrow-derived mast cells. 997 82

Human basophils represent a major source of interleukin (IL) 4 and 13 protein, cytokines which share several biological activities central to the pathogenesis of allergic inflammation. Studies show that the production of these cytokines differs with respect to mode of activation and the time course of their secretion. Pharmacologic evidence indicates that IL-4 generation, which is most prominent with IgE-dependent activation, is mediated through a calcineurin-dependent pathway. In contrast, multiple pathways seem evident in the regulation of IL-13 in basophils.
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PMID:Mechanisms and pharmacologic control of basophil-derived IL-4 and IL-13. 1022 47

Changes in the redox status of cells affect NF-kappaB and activator protein (AP)-1 nuclear expression and activity. In particular, antioxidants decrease NF-kappaB and increase AP-1 transcriptional activity, thereby regulating gene expression. In T cells, low concentrations of antioxidants enhance IL-2 and inhibit IL-4 expression. Since NFAT binding sites play an essential role in regulating IL-2 and IL-4 gene transcription, we studied the effects of dithiocarbamates, using the pyrrolidine derivative of dithiocarbamate (PDTC), on the activity of the distinct AP-1-containing IL-2 NFAT and AP-1-less IL-4 NFAT enhancers elements. Consistent with the presence of AP-1 proteins within the IL-2 NFAT complex, PDTC strongly enhanced phorbol 12-myristate 13-acetate/phytohemagglutinin-induced NFAT binding to the IL-2 NFAT enhancer and transcriptional activity of a reporter plasmid driven by this NFAT enhancer. In contrast, the activity of the IL-4 NFp enhancer, which does not bind AP-1, was abolished by PDTC treatment. In the Jurkat T cell line treated with PDTC, co-expression of the Ca2+/calmodulin-dependent phosphatase, calcineurin, completely restored the IL-4 NFp enhancer activity. Our data indicate that calcineurin-mediated NFAT activity is a target for antioxidants and provides new insights into the molecular mechanisms controlling differential cytokine gene expression.
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PMID:Divergent effects of dithiocarbamates on AP-1-containing and AP-1-less NFAT sites. 1022 86

Activation-induced cell death of T cells typically occurs late in the primary response after a prior proliferative response. Here, we describe a novel form of cell death in which purified naive murine CD4+ cells undergo apoptosis within 18 h in vitro after strong TCR ligation. Such rapid-onset TCR-mediated death of T cells does not involve cell division and is Fas-dependent, inhibited by CD28 (and IL-6) costimulation and enhanced by IL-4 and IL-7; by contrast, spontaneous death of CD4+ cells cultured alone is Fas-independent and inhibited by IL-4 and IL-7. TCR-mediated Fas-dependent death of CD4+ cells is prevented by combined TCR/Fas ligation and by drugs that inhibit calcineurin-dependent signaling and mitogen-activated protein kinase MEK1 activation.
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PMID:Strong TCR ligation without costimulation causes rapid onset of Fas-dependent apoptosis of naive murine CD4+ T cells. 1043 14

Hypothemycin, a resorcylic acid lactone antibiotic, was identified as active in a screen for inhibitors of T cell activation. It was found to inhibit the proliferation of mouse and human T cells stimulated with anti-CD3 mAb + PMA and of human PBMC stimulated with anti-CD3 mAb alone. This inhibition was partially reversed by exogenous IL-2 indicating that it is not due to non-specific toxicity. Hypothemycin potently suppressed the production of IL-2 (IC50: 9 nM) but affected IL-2-induced proliferation to a lesser extent (IC50: 194 nM). Hypothemycin also inhibited IL-6, IL-10, IFN-gamma and TNF-alpha production. By contrast, it markedly enhanced the production of IL-4, IL-5 and IL-13. These effects were seen both at the mRNA and protein secretion levels. Analysis of the effect of hypothemycin on CD69 induction suggested that it disrupts calcineurin-independent rather than calcineurin-dependent signaling. Furthermore, hypothemycin was able to inhibit the phosphorylation of ERK1/2 induced by PMA treatment of T cells. Therefore, hypothemycin represents an inhibitor of T cell activation with a novel mode of action and unique modulatory activity on cytokine production.
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PMID:Hypothemycin inhibits the proliferative response and modulates the production of cytokines during T cell activation. 1059 82

The mechanism by which glucocorticoids (GC) inhibit IL-4 gene expression is currently unknown. In T lymphocytes, IL-4 gene expression is regulated at the level of transcription by increases in intracellular calcium concentration and by the calcium-activated phosphatase calcineurin. In this paper we report that dexamethasone (Dex) inhibits calcium ionophore-induced activation of the human IL-4 promoter in transiently transfected Jurkat T cells. Inhibition of the promoter by Dex is dependent on expression of the GC receptor (GR), because it does not occur in GR-deficient cells. Dex also represses activation of the promoter induced by cotransfecting cells with a constitutively active mutant of calcineurin. Using a series of deletion constructs, we show that the proximal 95 bp of the IL-4 promoter contain a Dex-sensitive regulatory element. This region contains the P1 sequence, a proximal binding site for NF-AT. A calcium-induced but Dex-inhibited nuclear complex containing NF-AT binds to the P1 element in EMSA. Using immunoprecipitation under nondenaturing conditions, we found that the GRalpha isoform coprecipitates with NF-ATc in nuclear extracts of calcium ionophore- and Dex-treated cells. Taken together, our results show that GC inhibit IL-4 gene expression by interfering with NF-AT-dependent transactivation of the proximal human IL-4 promoter.
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PMID:Glucocorticoids inhibit calcium- and calcineurin-dependent activation of the human IL-4 promoter. 1062 28

Development of naive T cells into type 1 (Th1, Tc1) or type 2 (Th2, Tc2) effector cells is thought to be under the control of cytokines. In this study, we show that when both IL-12 and IL-4 are present, murine and human T cell differentiation is regulated by the balance of protein kinase C (PKC) and calcium signaling within T cells. Although both biochemical signals were required for T cell activation via the TCR, altering the balance between them redirected type 1 cells to type 2 and vice versa. Stimulation of calcium signaling or inhibition of PKC favored type 1 differentiation, whereas stimulation of PKC or inhibition of calcineurin resulted in type 2 effectors. Altered peptide ligands induced distinct balances of PKC/calcium signaling and altered Tc1/Tc2 development in TCR-transgenic CD8 T cells. The data suggest novel strategies for manipulation of the immune response in vivo.
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PMID:The balance of protein kinase C and calcium signaling directs T cell subset development. 1065 28


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