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)

We analyzed the effect of rapamycin on autocrine mast cell tumor lines with abnormally stable interleukin-3 (IL-3) transcripts due to a defect in mRNA degradation. Rapamycin inhibited IL-3 mRNA expression specifically, while transcripts of IL-4 and IL-6 were not affected. As indicated by the use of the transcriptional inhibitor actinomycin D or by reporter constructs, inhibition was posttranscriptional and resulted from destabilization of the mRNA. Transcripts from transgenes lacking the AU-rich 3' untranslated region were refractory to drug-induced degradation, suggesting that these 3' sequences contain the target of the rapamycin effect. Rapamycin did not promote IL-3 mRNA degradation in cells of a tumor variant lacking expression of FKBP12, the binding protein of rapamycin. Experiments with wortmannin indicated that rapamycin does not act via p70S6 kinase. FK-506, another ligand of FKBP12 affecting the phosphatase calcineurin, did not antagonize but shared the effect of rapamycin. Our data fit a model whereby both FKBP12 and calcineurin target an unknown regulator of IL-3 mRNA turnover.
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PMID:Rapamycin destabilizes interleukin-3 mRNA in autocrine tumor cells by a mechanism requiring an intact 3' untranslated region. 915 24

Productive T cell activation leading to cytokine secretion requires the cooperation of multiple signaling pathways coupled to the TCR and to costimulatory molecules such as CD28. Here, we utilized two pharmacophores, PD98059 and FK506, that inhibit, respectively, mitogen-activated protein (MAP) kinase kinase 1 (MEK 1) and calcineurin, to determine the relative role of the signaling pathways controlled by these enzymes in T cell activation. Although the two compounds had distinctive effects on CD69 induction, they both suppressed T cell proliferation induced by anti-CD3 mAb, in a manner reversible by exogenous IL-2, suggesting that PD98059, like FK506, affects the production of, rather than the responsiveness to growth-promoting cytokines. Accordingly, IL-2 production by T cells stimulated with anti-CD3 mAb in conjunction with PMA or with anti-CD28 mAb was inhibited by both compounds. However, these compounds differentially affected the production of other cytokines, depending on the mode of activation. PD98059 inhibited TNF-alpha, IL-3, granulocyte-macrophage (GM)-CSF, IFN-gamma, and to a lesser extent IL-6 and IL-10 production but enhanced IL-4, IL-5, and IL-13 production induced by CD3/PMA or CD3/CD28. FK506 suppressed CD3/PMA-induced production of all cytokines examined here but to a lesser extent IL-13. FK506 also reduced CD3/CD28-induced production of IL-3, IL-4, IL-10, TNF-alpha, and IL-6 but augmented that of GM-CSF, IL-5, IFN-gamma, and IL-13. Therefore, the biochemical targets of PD98059 and FK506 contribute differently to the production of various cytokines by T cells, which may have implications for the therapeutic manipulation of this production.
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PMID:Inhibition of T cell activation by pharmacologic disruption of the MEK1/ERK MAP kinase or calcineurin signaling pathways results in differential modulation of cytokine production. 951 Jan 55

IL-6 is a pleiotropic cytokine that modulates the diverse functions of hepatocytes such as acute phase responses and inflammation. When human hepatoma cells, Hep3B cells, were treated with IL-6, p140 was phosphorylated rapidly and reached its maximal rate at 1 min after treatment. Okadaic acid, an inhibitor of protein phosphatase 1 and 2A, affected IL-6-induced p140 phosphorylation. Interferon regulatory factor-1 (IRF-1) is a transcription factor on the enhancer of type I interferons, and its gene expression is induced by IL-6. When IRF-1 promoter-luciferase construct was transfected into Hep3B cells, okadaic acid increased IL-6- induced IRF-1 promoter activity. In addition, co-transfection of protein phosphatase 2A (PP2A) antisense constructs further increased IL-6-induced IRF-1 promoter activity, suggesting that PP2A is involved in IL-6 signaling. In addition, IL-6 directly induced the PP2A phosphorylation. PP2A phosphorylation was maximal at 1 min after IL-6 stimulation, but it was not induced by other inflammatory cytokines such as TNF-alpha or TGF-beta. Furthermore, IL-6 activated PP2A activity simultaneously. Taken together, these data indicate that IL-6 modulates the functions of PP2A which is involved in downstream events of IL-6 signaling in Hep3B.
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PMID:Roles of protein phosphatase 2A in IL-6 signal transduction in Hep3B cells. 965 61

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

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. 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. The ERK pathway-specific inhibitor PD98059 inhibited IL-6 secretion from monocytes. 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. 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. 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. 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. Our results suggest that the JNK pathway may regulate NF-kappa B-mediated gene transcription through its phosphorylation and activation of c-Jun.
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PMID: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. 1020 34

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

Ca(2+)-mobilizing compounds such as the Ca(2+) ionophore A23187 or the endoplasmic reticulum Ca(2+) ATPase inhibitor thapsigargin can suppress or induce apoptosis in the same cells. The use of different calcineurin inhibitors has shown that both suppression and induction of apoptosis by the Ca(2+)-mobilizing compounds were mediated by calcineurin activation. Ca(2+)-mobilizing compounds activated p38 and p44/42 mitogen-activated protein kinases (MAPKs). Induction of apoptosis by the Ca(2+)-mobilizing compounds was suppressed by an inhibitor of p38 MAPK but not by an inhibitor of p44/42 MAPK. These MAPK inhibitors did not suppress apoptosis induction by wild-type p53 or by withdrawal of IL-6 from IL-6-dependent cells that are mediated by calcineurin-independent pathways. These MAPK inhibitors also did not affect the ability of Ca(2+)-mobilizing compounds to suppress apoptosis. The results indicate that (i) Ca(2+)- mobilizing compounds activate different and opposing pathways that diverge downstream from calcineurin activation that can either suppress or induce apoptosis in the same cells; (ii) p38 MAPK but not p44/42 MAPK is involved in induction of apoptosis but not in its suppression by the Ca(2+)-mobilizing compounds; and (iii) neither p38 nor p44/42 MAPKs mediate induction of apoptosis by some calcineurin-independent pathways.
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PMID:Suppression or induction of apoptosis by opposing pathways downstream from calcium-activated calcineurin. 1051 68

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

Corticosteroids and the calcineurin inhibitors cyclosporin A (CsA) and FK506 have been studied extensively regarding their effects on T lymphocytes, but their effects on dendritic cells (DC) are relatively unknown. Monocytes are one of the precursors of DC that differentiate into CD14-CD1a+ immature DC upon culture with IL-4 and GM-CSF. The presence of CsA or FK506 during differentiation did not affect DC development. In contrast, the presence of corticosteroids, either dexamethasone (Dex) or prednisolone (Pred), for as little as the first 48 h of culture blocked the generation of immature DC. Dex-DC were unresponsive to signals inducing maturation (CD40 ligand, lipopolysaccharide), as demonstrated by the absence of CD83, CD80/CD86 and HLA-DR up-regulation and their strongly reduced T cell stimulatory capacity. Furthermore, Dex-DC showed a decreased CD40 ligand-induced IL-6 and TNF-alpha production, a complete block in IL-12p40 production, while IL-10 production was unaffected. CsA-DC and FK506-DC showed a partial reduction in the production of TNF-alpha, whereas all other functional activities appeared to be similar to control DC. These data show that, when compared to calcineurin inhibitors, corticosteroids have a unique and profound inhibitory effect on the generation and function of DC.
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PMID:The effect of calcineurin inhibitors and corticosteroids on the differentiation of human dendritic cells. 1094 Aug 69

Interleukin (IL)-4 and IL-12 together with T cell receptor (TCR) engagement are crucial for the differentiation of CD4(+) T cells into T helper (Th)2 or Th1 cells, respectively. Although IL-4 receptors (IL-4Rs) but not IL-12Rs are expressed on naive CD4(+) T cells, IL-4 has no apparent advantage over IL-12 in driving naive T cell differentiation when the cells are primed with both IL-4 and IL-12 in vitro. It was found that IL-4-induced phosphorylation of Janus kinases 1 and 3, IL-4R alpha, signal transducer and activator of transcription 6, and insulin receptor substrate 2 was strikingly but transiently inhibited by TCR ligation both in conventional and TCR transgenic T cells. TCR engagement also blocked the expression of an IL-4-inducible gene. Signals induced by other cytokines, including IL-2, IL-6, and interferon alpha, but not by insulin-like growth factor 1, were also blocked by TCR engagement. The capacity of various inhibitors to reverse TCR-mediated inhibition of IL-4 signaling suggested that activation of the Ras-mitogen-activated protein kinase pathway and of the calcineurin pathway contribute to desensitizing IL-4R. IL-4 responsiveness returned at about the time ( approximately 12 h) that IL-12-mediated signaling was first observed. Thus, through different mechanisms, neither IL-4R nor IL-12R has any clear advantage in polarizing cells; rather, the availability of cytokine is probably the limiting factor in this process.
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PMID:Transient inhibition of interleukin 4 signaling by T cell receptor ligation. 1103 2


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