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)

A few protein targets were found to display a specific high-affinity interaction with the immunosuppressant cyclosporin A (CsA): cytosolic cyclophilins (CyP)A, B, C, D, E containing from 122 to 174 amino acid residues in a polypeptide chain, and secreted forms of CyP; CyP-40, 40-kDa CsA-binding polypeptide complexed with steroid receptor (SR); CyP-related 150-kDa receptor of natural killer (NK) cells; interleukin 8 (IL-8); actin; a family of molecular chaperones hsp70 and P-glycoprotein (P-GP). All CyPs possess peptidyl-prolyl cis-trans isomerase activity (PPIase) and may serve as ATP-independent molecular chaperone proteins. The CsA-CyP complexes are specific inhibitors of Ca(2+)-and calmodulin-dependent protein phosphatase calcineurin (CaN). The inhibition of CaN blocks the activation of genes of IL-2, IL-2R, IL-4, etc. in T cells. In addition, immunosuppressive and/or antiinflammatory activity of CsA can be executed via CyP-40 and hsp 70 complexed with SR, and following the interaction with CyP-related receptor of NK and with IL-8. CsA binding to CyPC, P-GP and actin may throw light on the biochemical events leading to nephrotoxicity and graft vessel disease, two major side effects produced by CsA. The discovery of the interaction of human immunodeficiency virus type 1 (HIV-1) Gag protein with CyP and effective disruption of this interaction by CsA may be important for our understanding of the pathology caused by this immunosuppressive virus and will inspire therapeutic strategies to nip HIV in the bud. Bacterial immunophilins (ImPs) contribute to the virulence of pathogenic microorganisms. Elucidation of molecular mechanisms of microbial ImPs' action in the pathogenesis of bacterial infections may lead to new strategies for designing antibacterial drugs.
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PMID:Some new aspects of molecular mechanisms of cyclosporin A effect on immune response. 754 42

In order to evaluate the functional role of chemotactic cytokines in the regulation of brain function, we examined the effects of acidosis on the production of IL-8 in cultured neurons and/or astrocyte-rich cerebellar granule cells as assessed by the ELISA method. A time-dependent and significant production of IL-8 was detected in the extracellular fluid of astrocyte-rich cultured cells at 2, 3 and 6 hrs after treatment with acidified Krebs-HEPES buffer (pH 6.9), although such production did not appear in the fluid of neuron-rich cells. Additionally, microglia were detected by microscopic examination in both cultured cells under acidotic conditions. Only astrocyte-containing cultured cells produced a marked increase in intracellular IL-8 under acidotic conditions, although this production was much less than that seen in the extracellular fluid at 6 hrs under acidosis. The increase of IL-8 in astrocyte-rich cultures induced by acidosis was potentiated by treatment with glutamate, which enhanced the increase of cytosolic Ca2+ levels under acidosis, and was affected by extracellular Ca2+ conditions, by cyclosporine A, an inhibitor of calcineurin, and by trifluoperazine, an inhibitor of phospholipase A2. Significant inhibition of IL-8 production was detected after 6 hrs of pretreatment with trifluoperazine. Furthermore, the production of IL-8 under acidosis was associated with the appearance of astrocyte damage. These results suggest that Ca2+-dependent IL-8 is produced by astrocytes, but not neuronal cells, under acidosis, and that this production may be related to the process of cell dysfunction resulting from membrane destruction induced by acidosis.
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PMID:Extracellular presence of IL-8 in the astrocyte-rich cultured cerebellar granule cells under acidosis. 974 26

IL-8, a potent neutrophil chemoattractant that is elevated about 200-fold in exudative neutrophils isolated from localized inflammatory sites in vivo, is thought to play a major role in recruitment of neutrophils to inflammatory sites. Incubation of peripheral blood neutrophils with thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+-sequestering-ATPase, causes a dose-dependent induction of IL-8 synthesis that continues for up to 8 h. Cycloheximide inhibits the thapsigargin-induced IL-8 production, suggesting the induction of protein synthesis de novo. In addition, Northern blot analysis of mRNA isolated from neutrophils indicates that thapsigargin treatment increases IL-8 mRNA in a time- and dose-dependent manner. Thapsigargin also induces a biphasic rise in the intracellular Ca2+ concentration, [Ca2+]i, which is composed of an initial (within 15 s) EGTA-insensitive elevation in [Ca2+]i, followed by a delayed (2-min) EGTA-sensitive component. Addition of EGTA before thapsigargin inhibited the induction of IL-8 production. Experiments in which EGTA was added at various times after thapsigargin treatment indicated that a sustained Ca2+ influx was required for maximum IL-8 production. Ascomycin and cyclosporin A, inhibitors of the Ca2+-dependent phosphatase, calcineurin, also inhibited thapsigargin-induced IL-8 production. Thus, in neutrophils, a prolonged increase in [Ca2+]i stimulates IL-8 transcription and synthesis, possibly through a calcineurin-dependent pathway.
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PMID:Ca2+-dependent production and release of IL-8 in human neutrophils. 978 Feb 10

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

We have documented the time-dependent production of chemotactic cytokine, i.e., IL-8, in the extracellular fluid of astrocyte-rich cultured rat cerebellar granule cells under acidified conditions. In this paper, the mechanism of this production was evaluated based on the production of hydrogen peroxide (H2O2). Significant and time-dependent increases of cytosolic H2O2 were detected under acidosis in astrocyte-rich cultured cell. Upon exposure to 10 microM H2O2, significant levels of IL-8 appeared in the extracellular fluid of astrocyte-rich cells, although an initial transient increase of IL-8 was also seen in the intracellular space. Concurrently, after H2O2 exposure cell injury and a delayed increase of cytosolic Ca2+ levels were detected in astrocyte-rich cells. However, in the absence of extracellular Ca2+, the cell injury and the increase of IL-8 production were significantly attenuated. A synergistic effect of cyclosporine A (an inhibitor of the Ca2+/calmodulin-regulated protein phosphatase) and trifluoperazine (an inhibitor of phospholipase A2) on the suppression of H2O2-induced IL-8 production was clearly evident. These results suggest that extracellular acidosis induced Ca2+-dependent H2O2 production, which in turn stimulated IL-8 expression. which is regulated by the cytosolic Ca2+ cascade. Thus, the production of IL-8 from glia cells may have a role in regulating in the process of cell injury.
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PMID:Hydrogen peroxide induced chemokine production in the glia-rich cultured cerebellar granule cells under acidosis. 1183 44

Calcineurin (CaN), a calmodulin-dependent heterodimer, is, together with NAF-T, involved in the regulation of the Ca++ pump and in the transmission of the activation signal of the immune response. The CaN inhibitor drugs, such as cyclosporin A (CyA), carried by cyclophillin, and tacrolimus, carried by FK-binding protein-12 (FKBP-12), inhibit the binding with the regulatory subunit CaNB. A meta-analysis, comparing tacrolimus with cyclosporin A, has evidenced that tacrolimus significantly increases the diabetes prevalence one year after renal transplant. The diabetogenic effect is due to a direct effect of both drugs on the beta pancreatic cell, in particular on intracellular Ca++ metabolism, which is involved in the insulin secretion and in the reduction of the number of the secretor granules. Some immunological-hystochemical studies, performed on murine pancreas, have evidenced that the FKBP-12 content is higher in beta cells than in alpha cells. This fact allows a high intracellular store of tacrolimus, and a consequently more toxic effect, inside the insulin secreting structures. On the contrary, the low FKBP-12 content of alpha cells involves a higher content of calcineurin and a higher resistance to toxic effects. Finally, an increased incidence of islet cell antibodies (ICA) has been evidenced in patients treated with tacrolimus, as opposed to those treated with CyA.
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PMID:[Calcineurin inhibitors and mechanisms that are responsible for the appearance of post-transplant diabetes mellitus]. 1452 7

Interleukin (IL)-8 produced from glioblastoma is suggested to contribute to its own proliferation and progression. Since various external stimuli have been shown to increase intracellular Ca(2+) in glioma cells, we investigated Ca(2+) mobilization-dependent IL-8 expression and effect of cyclosporin A (CsA), an inhibitor of calcineurin (Cn), on the expression and invasive potential of human glioblastoma U251MG cells. Combined treatment with Ca(2+)-ionophore and phorbol-myristate-acetate (A23187/PMA) increased IL-8 mRNA and protein levels. This increase was suppressed by CsA and by another Cn inhibitor FK506. Luciferase reporter gene assay and electrophoretic mobility shift assay revealed that activation of p65-containing nuclear factor-kappaB was essential for A23187/PMA-dependent activation of IL-8 promoter. CsA suppressed the promoter activity by attenuating IkappaB-alpha degradation. U251MG cells expressed IL-8 receptors CXCR-1 and -2, and Matrigel invasion assay revealed that CsA attenuated A23187/PMA-dependent stimulation of invasive potential, probably by inhibiting IL-8 production. In addition, IL-8-dependent proliferation was also suppressed by CsA. Taken together, these results demonstrate the novel inhibitory effects of CsA on glioblastoma cell functions, suggesting CsA as a potential therapeutic adjuvant for glioma treatment.
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PMID:Inhibitory effects of cyclosporin A on calcium mobilization-dependent interleukin-8 expression and invasive potential of human glioblastoma U251MG cells. 1528 17

Cyclosporin A (CsA) blocks T cell activation by interfering with the Ca2+-dependent phosphatase, calcineurin. Proinflammatory responses to bacteria that are activated by Ca2+-fluxes in airway cells are a potential target for CsA. Although local immunosuppression may be advantageous to control airway inflammation, it could also increase susceptibility to bacterial pneumonia and invasive infection. As aerosolized CsA is currently under study in lung transplantation, we examined its direct effects on airway cells as well as in a murine model of pneumonia. Epithelial interleukin-6 production was very effectively inhibited by CsA, whereas CXCL8 production, the major PMN chemokine, was only modestly diminished. Responses to a TLR2 agonist Pam3Cys were more sensitive to CsA inhibition than those activated by Pseudomonas aeruginosa. CsA substantially blocked activation of nuclear factor of activated T cells and cAMP-responsive element-binding protein (P<0.001), inhibited CCAAT/enhancer-binding protein by 50% (P<0.05), and minimally blocked activator protein-1 and nuclear factor-kappaB responses to bacteria in epithelial cells. The in vitro effects were confirmed in a mouse model of P. aeruginosa infection with similar rates of PMN recruitment, pneumonia and mortality in CsA treated and control mice. These studies indicate that airway epithelial signaling is a potential target for CsA, and such local immunosuppression may not increase susceptibility to invasive infection.
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PMID:The effect of cyclosporin A on airway cell proinflammatory signaling and pneumonia. 1587 61

Cyclooxygenase (COX) is a key enzyme in prostaglandin (PG) synthesis. Up-regulation of COX-2 expression is responsible for increased PG release during inflammatory conditions and is thought to be also involved in allergic states. In this study, we demonstrate that in human T, B and natural killer lymphocytes from allergic patients, COX-2 expression became induced upon cell challenge with specific allergens and that this process is presumably IgE dependent and occurs after CD23 receptor ligation. This induction took place at both mRNA and protein levels and was accompanied by PGD2 release. IgE-dependent lymphocyte treatment elicited, in parallel, an activation of the MAPK p38 and extracellular signal-regulated kinase 1/2, an enhancement of calcineurin (CaN) activity, and an increase of the DNA-binding activity of the nuclear factor of activated T cells and of NF-kappaB, with a concomitant decrease in the levels of the cytosolic inhibitor of kappaB, IkappaB. In addition, specific chemical inhibitors of MAPK, such as PD098059 and SB203580, as well as MG-132, an inhibitor of proteasomal activity, abolished allergen-induced COX-2 up-regulation, suggesting that this process is mediated by MAPK and NF-kappaB. However, induction of COX-2 expression was not hampered by the CaN inhibitor cyclosporin A. We also examined the effect of a selective COX-2 inhibitor, NS-398, on cytokine production by human lymphocytes. Treatment with NS-398 severely diminished the IgE-dependently induced production of IL-8 and TNF-alpha. These results underscore the relevant role of lymphocyte COX-2 in allergy and suggest that COX-2 inhibitors may contribute to the improvement of allergic inflammation through the reduction of inflammatory mediator production by human lymphocytes.
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PMID:Induction of cyclooxygenase-2 expression by allergens in lymphocytes from allergic patients. 1599 64

Calcineurin inhibitors (CIs) cyclosporin and tacrolimus form the basis for immunosuppression in lung transplantation, yet also exert biological effects on nonlymphoid tissue. With the advent of inhaled cyclosporin, we hypothesize that the airway epithelium is also subject to CI effects at high doses. The aim of this study was to identify human tracheobronchial epithelial cell (hTBEC) calcineurin gene expression and quantify effects of CIs on hTBEC growth, interleukin-1-beta stimulated IL-8 production and hTBEC phenotype. Cyclophillin B and FK-associated binding protein, calcineurin A (alpha and beta), and NFATC3 and NFAT5 were detected in hTBEC cultures by RT-PCR. Acute and chronic cyclosporine treatment 1000 ng/mL significantly inhibited hTBEC proliferation, while tacrolimus did not (range of 10 ng/mL to 1000 ng/mL for acute treatment, 50 ng/mL for chronic treatment). Cyclosporin at 10,000 ng/mL significantly increased LDH release by well-differentiated hTBEC cultures (n = 6) and trended towards significance at 1000 ng/mL. IL1-beta stimulated IL-8 production was significantly increased in rapidly growing hTBEC cultures (n = 8) treated with cyclosporin (p = 0.049). Prolonged treatment of well-differentiated hTBECs at air-liquid-interface (ALI) with cyclosporin 1000 ng/mL significantly reduced intact multilayered mucociliary epithelium (p = 0.009). Inhibition of hTBEC growth, stimulation of IL-8 production and long-term effects on mucociliary phenotype and intact multi-layered epithelium suggest that cyclosporin may have a direct toxic effect on airway epithelium after transplantation.
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PMID:Calcineurin inhibitor effects on growth and phenotype of human airway epithelial cells in vitro. 1621 25


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