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)

Unexpected drug activities discovered during clinical testing establish the need for better characterization of compounds in human disease-relevant conditions early in the discovery process. Here, we describe an approach to characterize drug function based on statistical analysis of protein expression datasets from multiple primary human cell-based models of inflammatory disease. This approach, termed Biologically Multiplexed Activity Profiling (BioMAP), provides rapid characterization of drug function, including mechanism of action, secondary or off-target activities, and insights into clinical phenomena. Using three model systems containing primary human endothelial cells and peripheral blood mononuclear cells in different environments relevant to vascular inflammation and immune activation, we show that BioMAP profiles detect and discriminate multiple functional drug classes, including glucocorticoids; TNF-alpha antagonists; and inhibitors of HMG-CoA reductase, calcineurin, IMPDH, PDE4, PI-3 kinase, hsp90, and p38 MAPK, among others. The ability of cholesterol lowering HMG-CoA reductase inhibitors (statins) to improve outcomes in rheumatic disease patients correlates with the activities of these compounds in our BioMAP assays. In addition, the activity profiles identified for the immunosuppressants mycophenolic acid, cyclosporin A, and FK-506 provide a potential explanation for a reduced incidence of posttransplant cardiovascular disease in patients receiving mycophenolic acid. BioMAP profiling can allow integration of meaningful human biology into drug development programs.
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PMID:An integrative biology approach for analysis of drug action in models of human vascular inflammation. 1520 72

Recently, adenosine has been proposed to be a "metabolic" switch that may sense and direct immune and inflammatory responses. Inflammation and pro-inflammatory cytokine production are important in development of HIV-1 associated dementia, a devastating consequence of HIV-1 infection of the CNS. The HIV-1 protein Tat induces cell death in the CNS and activates local inflammatory responses partially by inducing calcium release from the endoplasmic reticulum. Because activation of adenosine receptors decreases production of the pro-inflammatory cytokine TNF-alpha in several experimental paradigms both in vitro and in vivo, we hypothesized that adenosine receptor activation would control both increased intracellular calcium and TNF-alpha production induced by Tat. Treatment of primary monocytes with Tat significantly increased the levels of intracellular calcium released from IP3 stores. Activation of adenosine receptors with CGS 21680 inhibited Tat-induced increases of intracellular calcium by 90 +/- 8% and was dependent on protein phosphatase activity because okadaic acid blocked the actions of CGS 21680. Tat-induced TNF-alpha production was inhibited 90 +/- 6% by CGS 21680 and concurrent treatment with okadaic acid blocked the inhibitory actions of CGS 21680. Using a model monocytic cell line, CGS 21680 treatment increased cytosolic serine/threonine phosphatase. Together, these data indicate that A2A receptor activation increases protein phosphatase activity, which blocks IP3 receptor-regulated calcium release and reduction of intracellular calcium inhibits TNF-alpha production in monocytes.
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PMID:Adenosine receptors control HIV-1 Tat-induced inflammatory responses through protein phosphatase. 1535 Dec 6

The Down syndrome critical region 1 (DSCR1) gene (also known as MCIP1, Adapt78) encodes a regulatory protein that binds to calcineurin catalytic A subunit and acts as a regulator of the calcineurin-mediated signaling pathway. We show in this study that DSCR1 is greatly induced in endothelial cells in response to VEGF, TNF-alpha, and A23187 treatment, and that this up-regulation is inhibited by inhibitors of the calcineurin-NFAT (nuclear factor of activated T cells) signaling pathway as well as by PKC inhibition and a Ca(2+) chelator. We hypothesized that the up-regulation of DSCR1 gene expression in endothelial cells could act as an endogenous feedback inhibitor for angiogenesis by regulating the calcineurin-NFAT signaling pathway. Our transient transfection analyses confirm that the overexpression of DSCR1 abrogates the up-regulation of reporter gene expression driven by both the cyclooxygenase 2 and DSCR1 promoters in response to stimulators. Our results indicate that DSCR1 up-regulation may represent a potential molecular mechanism underlying the regulation of angiogenic genes activated by the calcineurin-NFAT signaling pathway in endothelial cells.
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PMID:VEGF selectively induces Down syndrome critical region 1 gene expression in endothelial cells: a mechanism for feedback regulation of angiogenesis? 1535 55

Ethanol is known to increase susceptibility to infections, in part, by suppressing macrophage function. Through TLRs, macrophages recognize pathogens and initiate inflammatory responses. In this study, we investigated the effect of acute ethanol exposure on murine macrophage activation mediated via TLR2, TLR4, and TLR9. Specifically, the study focused on the proinflammatory cytokines IL-6 and TNF-alpha and activation of p38 and ERK1/2 MAPKs after a single in vivo exposure to physiologically relevant level of ethanol followed by ex vivo stimulation with specific TLR ligands. Acute ethanol treatment inhibited IL-6 and TNF-alpha synthesis and impaired p38 and ERK1/2 activation induced by TLR2, TLR4, and TLR9 ligands. We also addressed the question of whether ethanol treatment modified activities of serine/threonine-specific, tyrosine-specific phosphatases, and MAPK phosphatase type 1. Inhibitors of three families of protein phosphatases did not restore ethanol-impaired proinflammatory cytokine production nor p38 and ERK1/2 activation. However, inhibitors of serine/threonine protein phosphatase type 1 and type 2A significantly increased IL-6 and TNF-alpha levels, and prolonged activation of p38 and ERK1/2 when triggered by TLR4 and TLR9 ligands. In contrast, with TLR2 ligand stimulation, TNF-alpha production was reduced, whereas IL-6 levels, and p38 and ERK1/2 activation were not affected. In conclusion, acute ethanol exposure impaired macrophage responsiveness to multiple TLR agonists by inhibiting IL-6 and TNF-alpha production. Mechanism responsible for ethanol-induced suppression involved inhibition of p38 and ERK1/2 activation. Furthermore, different TLR ligands stimulated IL-6 and TNF-alpha production via signaling pathways, which showed unique characteristics.
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PMID:In vivo ethanol exposure down-regulates TLR2-, TLR4-, and TLR9-mediated macrophage inflammatory response by limiting p38 and ERK1/2 activation. 1561 Dec 71

Tacrolimus (FK506) is an immunosuppressive drug, widely used for organ transplantation and atopic dermatitis. Tacrolimus exerts its immunosuppressive effects primarily by interfering with the activation of T cells, via inhibition of calcineurin. Recent clinical studies have also demonstrated the efficacy of tacrolimus in the treatment of rheumatoid arthritis (RA), an autoimmune disease in which T cells play a pivotal role in pathogenesis. Inflammatory cytokines such as TNF-alpha, IL-1 beta, and IL-6 are involved in development of the disease. Recently, modes of action of tacrolimus on RA have been intensively studied in in vitro and animal arthritis models, demonstrating that tacrolimus exerts various novel actions as an anti-rheumatic drug. The pharmacological action of tacrolimus suggests that it has potential to specifically suppress the production of pathogenic inflammatory cytokines with a low frequency of infection, improve joint inflammation and bone/cartilage destruction, fully recover loss of functional status, exert rapid relief in arthritic pain, and promote osteogenic and chondrogenic differentiation. Here we review the action of tacrolimus on experimental models of RA, with a focus on our recent studies, and provide further insight into experimental models used for identifying efficacious anti-rheumatic drugs.
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PMID:A review of the action of tacrolimus (FK506) on experimental models of rheumatoid arthritis. 1572 98

Polyamine depletion prevents apoptosis by increasing serine/threonine phosphorylation leading to either inactivation or activation of pro- and anti-apoptotic proteins, respectively. Despite evidence that protein kinases are regulators of apoptosis, a specific role for protein phosphatases in regulating cell survival has not been established. In this study, we show that polyamine depletion inhibits serine/threonine phosphatase 2A (PP2A). Inhibition of PP2A in cells depleted of polyamines correlated well with increased phosphorylation of Bad at Ser112. Bad Ser112 phosphorylation in response to tumor necrosis factor (TNF)-alpha treatment decreased with time in cells grown in control as well as those grown in the presence of alpha-difluoromethylornithine plus putrescine. However, a sustained increase in the levels of Bad Ser112 phosphorylation was maintained in response to TNF-alpha treatment in cells grown in the presence of alpha-difluoromethylornithine. Inhibition of PP2A by okadaic acid and fostriecin or PP2A small interfering RNA transfection significantly decreased TNF-alpha-induced apoptosis in control and polyamine-depleted cells. Inhibition of PP2A by okadaic acid: 1) increased Bad and Bcl-2 phosphorylation at Ser112 and Ser70, respectively; 2) increased ERK activity; 3) prevented JNK activation; 4) prevented cytochrome c release, and activation of caspases-9 and -3 in response to TNF-alpha. Inhibition of MEK1 by U0126 prevented phosphorylation of Bad at Ser112. These results indicate that polyamines regulate PP2A activity, and inhibition of PP2A in response to polyamine depletion increases steady state levels of Bad and Bcl-2 proteins and their phosphorylation and thereby prevents cytochrome c release, caspase-9, and caspase-3 activation.
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PMID:Protein phosphatase 2A regulates apoptosis in intestinal epithelial cells. 1599 15

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

Microglia are phagocytic cells in the CNS and actively participate in proinflammatory responses in neurodegenerative diseases. We have previously shown that TNF-alpha up-regulated the expression of formyl peptide receptor 2 (mFPR2) in mouse microglial cells, resulting in increased chemotactic responses of such cells to mFPR2 agonists, including amyloid beta1-42 (Abeta42), a critical pathogenic agent in Alzheimer's disease. In the present study, we found that IL-4, a Th2-type cytokine, markedly inhibited TNF-alpha-induced expression of mFPR2 in microglial cells by attenuating activation of ERK and p38 MAPK as well as NF-kappaB. The effect of IL-4 was not dependent on Stat6 but rather required the protein phosphatase 2A (PP2A) as demonstrated by the capacity of PP2A small interfering RNA to reverse the effect of IL-4 in TNF-alpha-activated microglia. Since both IL-4 and TNF-alpha are produced in the CNS under pathophysiological conditions, our results suggest that IL-4 may play an important role in the maintenance of CNS homeostasis by limiting microglial activation by proinflammatory stimulants.
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PMID:IL-4 inhibits the expression of mouse formyl peptide receptor 2, a receptor for amyloid beta1-42, in TNF-alpha-activated microglia. 1623 6

Pharmacotherapy of autoimmune thyroid disease (AITD) is complex. Apart from the replacement hormone therapy, antithyroid agents, beta adrenoceptor blockers and other drugs, in regard to the present symptoms, it also includes the administration of glucocorticoids and immunosuppressive agents. Physiological actions of glucocorticoids are significant in number, well known and described in details. The most prominent pharmacological properties of glucocorticoids, that are important fortheir clinical use, are antiinflammatory and immunosuppressive actions. In this article, the most notable clinical pharmacology aspects of glucocorticoids have been presented, including the basic principles of their therapeutic use, as well as the most important indications with the examples of dosing regiments (rheumatic disorders, renal diseases, allergic reactions, bronchial asthma, gastrointestinal inflammatory diseases, thrombocytopenia, organ transplantation, and Graves' ophthalmopathy). In addition, adverse and toxic effects of glucocorticoids as well as their interactions with other drugs have been described. Immunosuppressive agents have important role in treatment of immune disorders, including the reduction of immune response in autoimmune diseases and organ transplantation. Apart from glucocorticoids, immunosuppressive agents consist of calcineurin inhibitors (cyclosporine, tacrolimus), antiproliferative and antimetabolic agents (sirolimus, azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide), monoclonal antibodies: anti-CD3 antibody (muromonab-CD3), anti-CD25 antibody (daclizumab), anti-TNF-alpha antibody (infliximab). In this part, the most updated facts about mechanism of action, rational therapeutic use, as well as adverse and toxic effects of immunosuppressive agents have been reviewed.
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PMID:[Therapeutic use of glucocorticoids and immunosuppressive agents]. 1640 60

We report induction of TNF-alpha via the calcium/calcineurin/NFAT pathway in PC12 neural cells. In PC12, expression of TNF-alpha mRNA, protein and TNF-alpha gene promoter activity was induced by co-stimulation with phorbol ester and either calcium ionophore A23187 or the L-type Voltage Gated Calcium Channel agonist Bay K 8644. Pre-treatment with calcineurin inhibitors CsA or FK506 inhibited the dominant calcium-dependent component of this induction, limiting it to the level achieved with phorbol ester alone. Promoter activation by Bay was abolished by nifedipine, a specific inhibitor of L-type Voltage Gated Calcium Channels. Exogenous NFAT protein transactivated the TNF-alpha promoter, and the peptide VIVIT-a specific inhibitor of calcineurin/NFAT binding-blocked calcium-inducible transactivation of the TNF-alpha promoter. Given proposed functions of TNF-alpha in spatial learning, memory and the pathogenesis of neurodegenerative diseases, the data presented suggest an important role for calcineurin/NFAT signaling in these key neurological processes.
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PMID:Calcium-dependent expression of TNF-alpha in neural cells is mediated by the calcineurin/NFAT pathway. 1645 16


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