Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin (IL)-10, an immunomodulatory cytokine predominantly produced by monocytes/macrophages and T cells, inhibits several functions of dendritic cells (DC), monocytes and T cells including their cytokine production, but it stimulates B cell immunoglobulin (Ig) production and cytotoxic T lymphocyte (CTL) generation. A precise knowledge of the mechanisms that control the IL-10 production is therefore highly important for understanding the immunoregulation. The IL-10 production was studied in cultures of freshly isolated human T cells. A rise in intracellular calcium as well as the common gamma-chain containing cytokine receptor triggering or CD28 triggering were found to be important signals for IL-10 induction. CD80, CD58, rIL-12 and rIFN-alpha all had efficacious and independent costimulatory activities on the IL-10 production, while PGE2 was inhibitory. Dependence on autocrine IL-2 signalling was shown by the effects of anti-IL-2 and anti-IL-2R monoclonal antibodies (MoAb), but the IL-10 production proceeded partly IL-2-independent when CD80 provided costimulation. Sensitivity to inhibition by CsA was not removed by CD80 or CD58 costimulation and/or by addition of rIL-12 or rIFN-alpha, pointing to the absolute requirement for calcineurin activity. These data reveal important differences in the regulatory pathways between IL-10 (a cytokine-inhibitory interleukin) and IL-2 (a cytokine-inducing interleukin), which can potentially be exploited therapeutically. The fact that CsA blocks the production of IL-10, which itself has important immunosuppressive properties, should be taken into account in defining immunosuppressive treatment schedules which include the use of CsA.
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PMID:Regulation of the IL-10 production by human T cells. 1116 17

The chemokine superfamily consists of small (8-10 kDa) molecules that function to attract, selectively, different subsets of leukocytes. Binding of chemokines to their appropriate G-protein-coupled receptors is necessary for primary immune responses and for homing of leukocytes to lymphoid tissues. Here, we have characterized the signaling pathways in primary T lymphocytes that regulate chemokine gene induction using an RNase protection assay. Dependence on stimulation through the coreceptor CD28 and sensitivity to the calcineurin inhibitors cyclosporine and tacrolimus were studied using purified human peripheral blood lymphocytes. Lymphotactin (Ltn), macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta were all rapidly induced and sensitive to cyclosporine treatment. At later time points, the expression of MIP-1alpha and MIP-1beta, but not of Ltn, was restored despite the inhibition of calcineurin activity. By contrast, the induction of interleukin-8 was delayed and was found to be cyclosporine insensitive. Calcineurin activity of IP-10 mRNA induction was contingent on the specific T-cell stimulation conditions, suggesting that IP-10 expression is modulated by calcineurin-dependent and -independent signaling pathways. Differential chemokine expression profiles result from the engagement of T-cell coreceptors and the requirement for, and the dependence on, calcineurin phosphatase activity.
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PMID:Differential chemokine expression profiles in human peripheral blood T lymphocytes: dependence on T-cell coreceptor and calcineurin signaling. 1239 16

Immunophilin ligands, cyclosporine A and FK506 (tacrolimus), besides their immunosuppressive action, have several effects on different neural functions, such as modulation of the release of many neurotransmitters, the reduction of nitric oxide (NO) production by the inhibition of dephosphorylation of neuronal nitric oxide synthase (nNOS) and the alteration of the expression of certain genes. Many of these actions apparently occur through the inhibition of calcineurin, a calcium-calmodulin-dependent phosphatase. On the other hand, several studies have shown that NO has a critical role in opioid-induced tolerance and dependence in both in vivo and in vitro models. In the present study, the effect of cyclosporine A and FK506 on the development of tolerance to and dependence on morphine in the guinea pig ileum was assessed. Morphine inhibited electrically stimulated twitch of ileum in a concentration-dependent manner (pD(2)=7.45+/-0.07). Tolerance to this effect was induced by incubation of ileum with 2 x IC(50) or 4 x IC(50) of morphine for 2 h that induced a degree of tolerance of 6.81 and 18.10, respectively. The co-incubation of ileum with morphine along with either cyclosporine A or FK506 reduced the degree of tolerance significantly (P<0.05) and restored the sensitivity of ileum to the morphine inhibitory effect. Dependence was induced by incubation with 4 x IC(50) of morphine for 2 h and was assessed based on naloxone-induced contractions (10(-5) M). Cyclosporine A (10(-9) M) and FK506 (10(-9) M) can attenuate the development of dependence to morphine as shown by the significant decrease in naloxone-induced contractions (P<0.05). These results suggest that immunophilin ligands at very low concentrations (nanomolar) can reduce the induction of acute tolerance to and dependence on morphine in the myenteric plexus of guinea pig ileum.
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PMID:Inhibition by immunophilin ligands of morphine-induced tolerance and dependence in guinea pig ileum. 1270 76