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)

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

We have previously shown that the DNA binding activity of the transcription factor NFAT which plays a predominant role in IL-2 transcription decreases with age. Because the transactivation (dephosphorylation and nuclear translocation) of the NFAT-c (cytoplasmic component of the NFAT complex) is mediated by the calcium/calmodulin-dependent phosphatase, calcineurin (CaN), and because Ca2+/calmodulin-dependent kinases (CaMK-II and IV/Gr) have been shown to play a critical role in calcium signaling in T cells, it was of interest to determine what effect aging has on the activation and the levels of these calcium regulating enzymes. The induction of calcineurin phosphatase activity, and CaMK-II and IV/Gr activities, were studied in splenic T cells isolated from Fischer 344 rats at 6, 15, and 24 months of age. In addition, the changes in the protein levels of these enzymes were measured by Western blot. The calcineurin phosphatase activity and CaMK-II and IV kinase activities were at a maximum after the cells were incubated with anti-CD3 antibody for 5-10 minutes. The induction of calcineurin activity by anti-CD3 and by calcium ionophore (A23187) declined 65 and 55%, respectively, between 6 and 24 months of age. The induction of CaMK-IV activity, but not CaMK-II activity by anti-CD3, was significantly less (by 54%) in T cells from old rats compared to T cells from young rats. The decline in the activation of these enzymes with age was not associated with changes in their corresponding protein levels. These results demonstrate that alterations in calcineurin phosphatase activity and CaMK-IV activity may contribute to the well-documented age-related decline in T cell function.
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PMID:Age-related decline in activation of calcium/calmodulin-dependent phosphatase calcineurin and kinase CaMK-IV in rat T cells. 1065 83

The Vav protooncogene is a multidomain protein involved in the regulation of IL-2 gene transcription in T cells and the development of cell-mediated killing by cytotoxic lymphocytes. We have investigated the differential roles that specific protein subdomains within the Vav protooncogene have in the development of these two distinct cellular processes. Interestingly, a calponin homology (CH) domain mutant of Vav (CH-) fails to enhance NF-AT/AP-1-mediated gene transcription but is still able to regulate the development of cell-mediated killing. The inability of the CH- mutant to enhance NF-AT/AP-1-mediated transcription appears to be secondary to defective intracellular calcium, because 1) the CH- mutant has significantly reduced TCR-initiated calcium signaling, and 2) treatment with the calcium ionophore ionomycin or cotransfection with activated calcineurin restores NF-AT/AP-1-mediated gene transcription. The pleckstrin homology (PH) domain of Vav has also been implicated in regulating Vav activation. We found that deletion of the PH domain of Vav yields a protein that can neither enhance gene transcription from the NF-AT/AP-1 reporter nor enhance TCR- or FcR-mediated killing. In contrast, the PH deletion mutant of Vav is able to regulate the development of natural cytotoxicity, indicating a functional dichotomy for the PH domain in the regulation of these two distinct forms of killing. Lastly, mutation of three tyrosines (Y142, Y160, and Y174) within the acidic domain of Vav has revealed a potential negative regulatory site. Replacement of all three tyrosines with phenylalanine results in a hyperactive protein that increases NF-AT/AP-1-mediated gene transcription and enhances cell-mediated cytotoxicity. Taken together, these data highlight the differential roles that specific subdomains of Vav have in controlling distinct cellular functions. More broadly, the data suggest that separate lymphocyte functions can potentially be modulated by domain-specific targeting of Vav and other critical intracellular signaling molecules.
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PMID:Specific subdomains of Vav differentially affect T cell and NK cell activation. 1075 87

In clinical transplantation, the occurrence of cyclosporin A (CsA)-resistant production of IL-2 in vitro correlates with graft rejection in vivo. In this study we investigated the role of the costimulatory molecules CD28 and LFA-1 in this process in the setting of TCR-induced proliferation of primary T lymphocytes in vitro. Co-stimulation with ICAM-1 and B7.2 led to strong and CsA-resistant proliferation, which was found to be largely IL-2 dependent. All of the known calcineurin-dependent events, such as induction of NF-AT and NF-kappaB or stress-activated protein kinase activation, were markedly modulated by CsA independently of costimulation. In contrast, both ICAM-1 and B7.2 enhanced the half-life of the inducible IL-2 transcript in a CsA-resistant manner. LFA-1- but not CD28-induced IL-2 mRNA stabilization required the integrity of the actin-based cytoskeleton, suggesting that the two costimulatory molecules impact on qualitatively different signaling pathways. This is further suggested by the demonstration that LFA-1 and CD28 acted synergistically to confer CsA resistance in a model of co-stimulation using superantigen-pulsed dendritic cells. We propose that IL-2 transcript accumulation and subsequent T cell proliferation at the low transcriptional rate imposed by CsA are the result of co-stimulation-dependent stabilization of IL-2 mRNA.
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PMID:CD28 and LFA-1 contribute to cyclosporin A-resistant T cell growth by stabilizing the IL-2 mRNA through distinct signaling pathways. 1076 Aug 3

During the past 50 years, many immunosuppressive drugs have been described. Often their mechanisms of action were established long after their discovery. Eventually these mechanisms were found to fall into five groups: (i) regulators of gene expression; (ii) alkylating agents; (iii) inhibitors of de novo purine synthesis; (iv) inhibitors of de novo pyrimidine synthesis; and (v) inhibitors of kinases and phosphatases. Glucocorticoids exert immunosuppressive and anti-inflammatory activity mainly by inhibiting the expression of genes for interleukin-2 and other mediators. Cyclophosphamide metabolites alkylate DNA bases and preferentially suppress immune responses mediated by B-lymphocytes. Methotrexate and its polyglutamate derivatives suppress inflammatory responses through release of adenosine; they suppress immune responses by inducing the apoptosis of activated T-lymphocytes and inhibiting the synthesis of both purines and pyrimidines. Azathioprine metabolites inhibit several enzymes of purine synthesis. Mycophenolic acid and mizoribine inhibit inosine monophosphate dehydrogenase, thereby depleting guanosine nucleotides. Mycophenolic acid induces apoptosis of activated T-lymphocytes. A leflunomide metabolite and Brequinar inhibit dihydroorotate dehydrogenase, thereby suppressing pyrimidine nucleotide synthesis. Cyclosporine and FK-506 (Tacrolimus) inhibit the phosphatase activity of calcineurin, thereby suppressing the production of IL-2 and other cytokines. In addition, these compounds have recently been found to block the JNK and p38 signaling pathways triggered by antigen recognition in T-cells. In contrast, rapamycin inhibits kinases required for cell cycling and responses to IL-2. Rapamycin also induces apoptosis of activated T-lymphocytes. Immunosuppressive and anti-inflammatory compounds in development include inhibitors of p38 kinase and of the type IV isoform of cyclic AMP phosphodiesterase which is expressed in lymphocytes and monocytes.A promising future application of immunosuppressive drugs is their use in a regime to induce tolerance to allografts. The role of leukocytes in grafts, and the induction of apoptosis of clones of responding T-lymphocytes, is discussed.
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PMID:Immunosuppressive drugs: the first 50 years and a glance forward. 1087 84

We analysed regulatory mechanisms involved in the production of Th2 cytokines by freshly isolated human T cells. We used an in vitro culture system in which the primary signal was provided by a cross-linking anti-CD3 MoAb presented on the Fc receptors of P815 cells. Both CD80 and CD86, expressed on transfected P815 cells, were able to provide efficient costimulation for the production of IL-4, IL-5 and IL-13. IL-2 was also highly important for induction of all three Th2 cytokines. However, differences between IL-4 on the one hand and IL-5 and IL-13 on the other hand were observed when sensitivity to cyclosporin A (CsA) was studied. CsA (an inhibitor of calcineurin phosphatase activity) strongly inhibited IL-4 production, but it did either not affect or even increased IL-5 and IL-13 production. In accordance with this, CD80 and phorbol myristate acetate (PMA) (without anti-CD3 or calcium ionophore) were sufficient to induce production of IL-5 and IL-13, but not of IL-4. The subgrouping of Th2 cytokines was further confirmed at another level on the basis of differences in cell sources: IL-4 was predominantly produced by CD4+ T cells, while IL-5 and IL-13 were produced by both CD4+ and CD8+ T cells. Thus, differences in cell sources and in the requirement of the calcium/calcineurin-signalling pathway allowed us to identify two subgroups (IL-4 and IL-5/IL-13) among human Th2-type T cell cytokines.
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PMID:Differences in regulatory pathways identify subgroups of T cell-derived Th2 cytokines. 1088 43

A series of bis(trifluoromethyl)pyrazoles (BTPs) has been found to be a novel inhibitor of cytokine production. Identified initially as inhibitors of IL-2 synthesis, the BTPs have been optimized in this regard and even inhibit IL-2 production with a 10-fold enhancement over cyclosporine in an ex vivo assay. Additionally, the BTPs show inhibition of IL-4, IL-5, IL-8, and eotaxin production. Unlike the IL-2 inhibitors, cyclosporine and FK506, the BTPs do not directly inhibit the dephosphorylation of NFAT by calcineurin.
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PMID:3,5-Bis(trifluoromethyl)pyrazoles: a novel class of NFAT transcription factor regulator. 1095 6

Severe Combined Immunodeficiency (SCID) is a primary immunodeficiency affecting T cells, B cells, or both. Whereas the clinical symptoms are uniformly dominated by recurrent infections, the molecular causes for SCID are very heterogeneous. Mutations in cell surface receptors, signal transduction molecules and transcription factors have been described, including the common gamma chain of the IL-2 (and IL-4, IL-7, IL-9 and IL-15) receptors, the kinase JAK-3, the epsilon and gamma chains of CD3, the protein tyrosine kinase ZAP-70, as well as CIITA and RFX5 involved in MHC class II gene expression. In this work we describe two infants with SCID whose T cells display a severe defect in T cell activation and cytokine transcription due to impaired activation of the transcription factor NFAT. We show that this defect in activation is not due to mutations in the NFAT proteins expressed in T cells or the phosphatase calcineurin which regulates the activation of NFAT. However, nuclear import of NFAT in response to T cell activation was severely compromised in the patients' T cells. A modest degree of nuclear translocation of NFAT was achieved in the patients' T cells when nuclear export was inhibited using lithium chloride. This low level of nuclear NFAT in the nucleus was not sufficient to compensate for the defect in cytokine production in the patients' T cells. However, elevated levels of extracellular calcium led to an increase in cytokine gene transcription by the SCID T cells, suggesting that the underlying genetic defect in the patients involved calcium influx or the initiation of calcium signalling.
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PMID:Impaired NFAT regulation and its role in a severe combined immunodeficiency. 1099 88

C/EBP transcription factors have been described to control the activity of the human IL-4 promoter. The C/EBP binding sites within the IL-4 promoter overlap with composite NF-AT and AP-1 binding motifs. We show here that similar binding sites are part of the murine IL-4 promoter. Retroviral overexpression of C/EBPbeta in murine EL-4 thymoma cells led to a strong induction of endogenous IL-4 and a reduction in IL-2 and IFN-gamma expression. Similarily, in primary murine T cells C/EBPbeta induction resulted in an increase in IL-4 levels, whereas in human Jurkat T cells a decrease in IL-2 RNA was detected. Like AP-1, C/EBP factors belong to the large class of basic leucine zipper proteins. However, unlike AP-1, C/EBPbeta does not act in synergy with NF-AT in the induction of the murine IL-4 promoter. Instead, both factors compete in their binding to the P4/Pu-bD site, one of the most important sequence elements of the IL-4 promoter. Whereas NF-AT factors require high levels of free Ca2+ and calcineurin activity for induction, C/EBP induction in T cells is Ca2+/calcineurin independent. These observations suggest that various induction conditions lead to the activation of transcription factors, inducing IL-4 promoter activity at specific developmental stages of T cells.
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PMID:C/EBPbeta enhances IL-4 but impairs IL-2 and IFN-gamma induction in T cells. 1100 91

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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