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)

The Forkhead box protein P3 (FOXP3) is a master cell lineage modulator in CD4(+)CD25(+) natural regulatory T cell (Treg) development. The Treg set of cells, also called T suppressor cells, play an essential role in natural Treg-mediated suppression of various types of immune cells. Suppression can be manifest by a cell-cell contact set of events, and recent evidence also supports soluble mediators. FOXP3 was previous identified as a passive transcriptional repressor which associates with nuclear factor of activated T-cells, cytoplasmic, and calcineurin-dependent 2 (NFATc2) as well as several other transcriptional factors including nuclear factor kappa-B (NFkappaB) and acute myeloid leukemia 1(AML1)/runt-related transcription factor 1(RUNX1). We found FOXP3 could actively repress transcription by recruiting distinct histone acetyltransferases and histone deacetylases to function as a co-repressor complex. The identification of enzymatic factors operative as essential participants in FOXP3-mediated transcriptional repression provides a practical basis for therapeutically modulating the activity of FOXP3 in immune suppression. Here we briefly summarize recent progress in our understanding of the biochemistry of FOXP3-mediated transcriptional regulation.
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PMID:FOXP3 actively represses transcription by recruiting the HAT/HDAC complex. 1759 52

APCs, like T cells, are affected by calcineurin inhibitors. In this study, we show that calcineurin inhibitors efficiently block MHC-restricted exogenous Ag presentation in vivo. Mice were injected with clinical doses of tacrolimus (FK-506) followed by soluble OVA, and dendritic cells (DCs) were isolated from lymph nodes and spleens. The efficacy of OVA peptide presentation by DCs was evaluated using OVA-specific CD8 and CD4 T cells. Tacrolimus inhibited both class I- and class II-restricted DC presentation of OVA to T cells. Tacrolimus also inhibited both class I- and class II-restricted presentation of OVA in peritoneal macrophages isolated from mice injected with tacrolimus followed by soluble OVA. Tacrolimus-treated peritoneal macrophages, however, were able to present synthetic OVA peptide, SIINFEKL. Inclusion of cyclosporine A to biodegradable microspheres containing OVA greatly reduced their capacity to induce OVA-specific CTL response in mice. These findings provide novel insight into the mode of action of calcineurin inhibitors and have important implications for clinical immunosuppression regimens.
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PMID:Calcineurin inhibitors block MHC-restricted antigen presentation in vivo. 1794 43

A growing number of studies suggest that CD4(+)CD25(+) T regulatory (Treg) cells play a significant role to downregulate the immune response to alloantigens. In this study, we investigated the possible influence of immunosuppressive therapy, including cyclosporine (CsA) or rapamycin (sirolimus), on the level of CD4(+)CD25(+), CD4(+)CD25(+)FOXP3(+), and CD4(+)CD25(+)CTLA-4(+) T cells in the peripheral blood of renal allograft recipients. The study was performed on renal allograft recipients who displayed uneventful stable courses (RAR-S; n = 15) versus biopsy-proven chronic rejection (RAR-CH; n = 12). The patients were divided based on the immunosuppressive protocol: group 1 (prednisone+CsA+Aza) and group II (prednisone+sirolimus). The control group consisted of 10 healthy blood donors. We examined the expression of CD4, CD25, CTLA-4, and Foxp3 in peripheral blood T cells. Flow cytometry was performed with a FACSCalibur (BD Biosciences) instrument with data analyzed using Cell Quest software. The percentage of CD4(+)CD25(+)Foxp3(+) T cells in rapamycin (sirolimus) treated patients did not differ from that observed in healthy individuals, but was significantly higher compared with CsA-treated patients. CsA therapy resulted in a reduction in the percentage of CD4(+)CD25(+)CTLA-4(+) and CD4(+)CD25(+)Foxp3(+) regulatory T cells after renal transplantation in both groups (RAR-S and RAR-CH) compared with patients treated with rapamycin or to healthy donors. The type of immunosuppressive therapy (with or without calcineurin inhibitors) may have an important role in tolerance induction and graft function.
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PMID:The influence of immuosuppressive therapy on the development of CD4+CD25+ T cells after renal transplantation. 1802 68

CD4(+)CD25(+) regulatory T cells (Tregs) are potent modulators of immune responses. The transcriptional program distinguishing Tregs from the CD4(+)CD25(-) Th cells is unclear. NFAT, a key transcription factor, is reported to interact with forkhead box p3, allowing inhibitory and activating signals in T cells. In the current study, we hypothesize that distinctive NFAT regulation in Tregs as compared with Th cells, may contribute to specific functions of these cells. Tregs express basal levels of cytoplasmic NFATc1 and NFATc2. In contrast to Th cells, anti-CD3-mediated T cell activation did not induce nuclear translocation of NFATc1 or NFATc2 in Tregs. This effect was associated with altered regulation for NFAT in Tregs that included reduced calcium flux, diminished calcineurin activation, and increased activity of glycogen synthase kinase-3beta, a negative regulatory kinase for NFAT in Tregs relative to Th cells. These data suggested that NFAT inhibition in Th cells may induce regulatory function. Indeed, pharmacologically mediated NFAT inhibition induced Th cells to function as Tregs, an effect that was mediated by induction of membrane-bound TGF-beta on Th cells. Collectively, these data suggest that maintaining NFAT at basal levels is a part of the transcriptional program required for Tregs.
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PMID:Regulation of the NFAT pathway discriminates CD4+CD25+ regulatory T cells from CD4+CD25- helper T cells. 1803 93

We have developed a model of aortic allograft vasculopathy (AV) that uses mouse strains that are fully disparate at Class I, Class II and minor histocompatibility antigens. Acute rejection is ablated with therapeutic doses of the calcineurin inhibitor Cyclosporine A (CyA). In this way we successfully mimic human disease. Using this model we have demonstrated, with cell transfer models using highly purified T cell populations, that calcineurin inhibitors ablate CD4(+) T cell effector mechanisms. As such, in the presence of calcineurin inhibition, graft vasculopathy is dependent on CD8(+) T cell effector mechanisms. In this study we examine the etiology of graft vasculopathy by these CD8(+) T cells in the presence of calcineurin inhibition. We transferred CD8(+) T cells from CyA treated IFN-gamma deficient mice into immunodeficient mouse recipients of aortic allografts to demonstrate that IFN-gamma production by CD8(+) T cells is essential for the development of AV in the presence of calcineurin inhibition. Using two models of CTL ablation we also demonstrated that CTL activity by CD8(+) T cells is essential for the development of AV in the presence of calcineurin inhibition. This is in contrast to models without calcineurin inhibitor immunosuppression where either pathway is capable, by itself, of inducing AV. These data indicate that although calcineurin inhibition ablates CD4(+) T cell effects and weakens CD8(+) T cell pathways, the antigenic challenge of the graft is enough to induce sufficient responsiveness from CD8(+) T cells to induce robust AV.
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PMID:CD8(+) T cells mediate aortic allograft vasculopathy under conditions of calcineurin immunosuppression: role of IFN-gamma and CTL mediators. 1850 85

Interleukin-18 (IL-18), a product of dendritic cells (DC), is a pro-inflammatory cytokine involved in the pathogenesis of allograft rejection, vascular disease, arthritis and diabetes. Rapamycin (Rapa) is an immunosuppressant that inhibits T cell mTOR kinase activation. In contrast, Sanglifehrin A (SFA), is a cyclophilin-binding immunosuppressant that does not act on calcineurin phosphatases but appears to inhibit IL-2-dependent T cell proliferation. Rapa and SFA exert some immunosuppressive effects on DC by inhibiting IL-12 production, although their effects on DC have not been investigated as comprehensively as those on T cells. We aimed to determine the impact of these drugs on DC IL-18 synthesis in vivo and in vitro. We found in vivo that LPS-stimulated OX62(+) DC produced significantly more IL-18 mRNA, compared to OX62(+) DC depleted splenocytes (p<0.01) and non-LPS-stimulated OX62(+) DC (p<0.01). OX62(+)CD4(+) and OX62(+)CD4(-) cells produced similar amounts of IL-18 mRNA. Rapa and SFA, but not CsA, significantly inhibited IL-18 production from OX62(+) DC in vitro, in a dose-dependent manner (p<0.05). In vivo IL-18 production was also inhibited by Rapa and SFA in splenic OX62(+) DC (p<0.01). Finally, inhibition of IL-18 production by Rapa and SFA was independent of the FK506 or cyclophilin pathways, respectively. In conclusion, Rapa and SFA, but not CsA, block IL-18 production and this novel Rapa blockade effect on IL-18 may contribute to the ability of Rapa to inhibit chronic allograft nephropathy and restenosis.
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PMID:Dentritic cell derived IL-18 production is inhibited by rapamycin and sanglifehrin A, but not cyclosporine A. 1866 82

Pavlovian conditioning is one of the major neurobiological mechanisms of placebo effects, potentially influencing the course of specific diseases and the response to a pharmacological therapy, such as immunosuppression. In our study with behaviorally conditioned rats, a relevant taste (0.2% saccharin) preceded the application of the immunosuppressive drug cyclosporin A (CsA), a specific calcineurin (CaN) inhibitor. Our results demonstrate that through pavlovian conditioning the particular pharmacological properties of CsA can be transferred to a neutral taste, i.e., CaN activity was inhibited in splenocytes from conditioned rats after reexposure to the gustatory stimulus. Concomitant immune consequences were observed on ex vivo mitogenic challenge (anti-CD3). Particularly, Th1-cytokine, but not Th2-cytokine, production and cell proliferation were impeded. Appropriate pharmacological and behavioral controls certify that all these changes in T-lymphocyte reactivity are attributable to mere taste reexposure. Furthermore, the underlying sympathetic-lymphocyte interaction was revealed modeling the conditioned response in vitro. CaN activity in CD4(+) T lymphocytes is reduced by beta-adrenergic stimulation (terbutaline), with these effects antagonized by the beta-adrenoreceptor antagonist nadolol. In summary, CaN was identified as the intracellular target for inducing conditioned immunosuppression by CsA, contributing to our understanding of the intracellular mechanisms behind "learned placebo effects."
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PMID:Calcineurin inhibition in splenocytes induced by pavlovian conditioning. 1910 49

Differentiation and clonal expansion of Ag-activated naive T cells play a pivotal role in the adaptive immune response. T cell Ig mucin (Tim) proteins influence the activation and differentiation of T cells. Tim-3 and Tim-2 clearly regulate Th1 and Th2 responses, respectively, but the precise influence of Tim-1 on T cell activation remains to be determined. We now show that Tim-1 stimulation in vivo and in vitro induces polyclonal activation of T cells despite absence of a conventional TCR-dependent signal 1. In this model, Tim-1-induced proliferation is dependent on strong signal 2 costimulation provided by mature dendritic cells. Ligation of Tim-1 upon CD4(+) T cells with an agonist anti-Tim-1 mAb elicits a rise in free cytosolic calcium, calcineurin-dependent nuclear translocation of NF-AT, and transcription of IL-2. Because Tim-4, the Tim-1 ligand, is expressed by mature dendritic cells, we propose that interaction between Tim-1(+) T cells and Tim-4(+) dendritic cells might ensure optimal stimulation of T cells, when TCR-derived signals originating within an inflamed environment are weak or waning.
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PMID:Tim-1 signaling substitutes for conventional signal 1 and requires costimulation to induce T cell proliferation. 1915 84

The influence of signals transmitted by the phosphatase calcineurin and the transcription factor NFAT on the development and function of natural killer T (NKT) cells is unclear. In this report, we demonstrate that the transcription factor early growth response 2 (Egr2), a target gene of NFAT, was specifically required for the ontogeny of NKT cells but not that of conventional CD4(+) or CD8(+) T cells. NKT cells developed normally in the absence of Egr1 or Egr3, which suggests that Egr2 is a specific regulator of NKT cell differentiation. We found that Egr2 was important in the selection, survival and maturation of NKT cells. Our findings emphasize the importance of the calcineurin-NFAT-Egr2 pathway in the development of the NKT lymphocyte lineage.
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PMID:The gene encoding early growth response 2, a target of the transcription factor NFAT, is required for the development and maturation of natural killer T cells. 1922 50

Junctional adhesion molecule (JAM)-C is an Ig superfamily protein, which is involved in the regulation of various inflammatory and vascular events such as transendothelial leukocyte migration. JAM-C is expressed highly on the surface of endothelial cells and platelets, whereas expression in T lymphocytes is not well studied. To investigate the specific gene regulation of JAM-C in T lymphocytes, we determined JAM-C expression in quiescent and activated human T cells. Treatment with the polyclonal T cell activator PHA increased surface and total JAM-C expression in T cells time- and dose-dependently, as determined by flow cytometry and immunoblot analysis. In contrast, no up-regulation of JAM-A in activated T cells was detectable. The highest level of JAM-C up-regulation by PHA was observed in CD3(+)forkhead box P3(+) and CD4(+)CD25(high) T cells. Moreover, TCR activation with combined anti-CD3 and anti-CD28 stimulation induced JAM-C expression in T cells. JAM-C induction occurred at the mRNA level, suggesting a transcriptional regulatory mechanism of JAM-C expression. Accordingly, we studied the regulation of the human JAM-C gene promoter in transiently transfected T cells. Luciferase activity of a JAM-C promoter gene construct with three potential consensus sites for the transcription factor NFAT was induced markedly in activated T cells. Finally, pretreatment with two pharmacological inhibitors of calcineurin, cyclosporin A, and FK-506, but not with MAPK inhibitors, blocked JAM-C induction in activated T cells. In summary, JAM-C is up-regulated in activated human T lymphocytes via a transcriptional mechanism, suggesting a potential role of JAM-C in T cell functions.
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PMID:Transcriptional induction of junctional adhesion molecule-C gene expression in activated T cells. 1920 48


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