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)

For severe forms of psoriasis ciclosporin has now been proven to be a clinically effective therapeutic regimen. Beside inhibiting T-cell activation, ciclosporin exerts various effects on other cells of the immune system, e.g. Langerhans cells, mast cells and endothelial cells. The influence of ciclosporin on these cells may be relevant to an understanding of its beneficial effect in psoriasis treatment. New information about the molecular mechanism of action regarding calcineurin-regulated signal transduction pathways provide further insight into the pharmacological effects. On the basis of new findings concerning the mode of action of ciclosporin and the results of recent multicentre studies in psoriasis, new guidelines for therapy are given.
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PMID:[Concepts of the mechanisms of action of cyclosporin in psoriasis. A review with guidelines on therapy]. 839 87

Keratin K17, the myoepithelial keratin, is expressed in psoriasis but is not present in healthy skin. Psoriasis is associated with production of gamma interferon (IFN gamma), which induces the expression of keratin K17 by activating transcription factor STAT1. Our hypothesis states that the induction of K17 is specific for the inflammatory reactions associated with high levels of IFN gamma and activation of STAT1. One of the corollaries of the hypothesis is that the STAT1-activating cytokines should induce the expression of keratin K17, whereas those cytokines that work through other mechanisms should not. Furthermore, because the STAT activation pathway is dependent upon protein phosphorylation events, phosphorylation inhibitors should attenuate the induction of keratin K17, whereas protein phosphatase inhibitors should augment it. To test this hypothesis, we analyzed lesional samples of inflammatory diseases using immunofluorescence, transfected keratinocytes with K17 gene promoter DNAs in the presence of various cytokines, and followed nuclear translocation of STAT1 in keratinocytes using specific antibodies. Confirming the hypothesis, we found that K17 is induced in psoriasis and dermatitis caused by delayed type hypersensitivity, which are associated with high levels of IFN gamma, but not in samples of atopic dermatitis, which is not. Two cytokines, interleukin-6 and leukemia inhibitory factor, which can induce phosphorylation of STAT1, can also induce K17 expression, whereas interleukin-3, interleukin-4, interleukin-10, and granulocyte macrophage colony stimulating factor have no effect on K17 expression. As expected, staurosporine and genistein inhibited, whereas okadaic acid augmented, the induction of K17 by IFN gamma. Our data indicate that in inflammatory skin diseases, lymphocytes, through the cytokines they produce, differently regulate not only each other, but also keratin gene expression in epidermis one of their target tissues.
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PMID:Regulation of epidermal expression of keratin K17 in inflammatory skin diseases. 882 63

T cells expressing the appropriate T-cell receptor Vbeta chain proliferate in response to Staphylococcus enterotoxin A (SEA) pulsed antigen-presenting cells (APC), whereas other T cells do not (SEA "non-responders"). Activated human T cells express MHC class II molecules that are high affinity receptors for SEA. Here we show that, in the absence of APC, SEA induces a profound inhibition of IL-15-driven proliferation in MHC class II+, human SEA-"responder" T-cell lines. In contrast, proliferation induced by phorbol esther (PMA) was enhanced by SEA. The inhibitory effect on cytokine-mediated mitogenesis correlates with an inhibition of IL-2Rbeta expression and ligand-induced tyrosine phosphorylation of IL-2R. Cyclosporin A (CyA), an inhibitor of the protein phosphatase (PP2B) calcineurin, strongly inhibits the SEA-induced modulations of cytokine receptor expression. Moreover, CyA inhibits both the anti-mitogenic effect of SEA on cytokine-induced proliferation and the pro-mitogenic effect of PMA. In contrast, inhibitors of PP1, PP2A, protein kinase C (PKC), phosphatidyl-inositol-3-kinase (PI-3K) and mammalian target of rapamycin (mTOR) are unable to inhibit the effects of SEA. In a SEA "non-responder" T-cell clone obtained from the affected skin of a patient with psoriasis vulgaris, SEA does not inhibit IL-2Rbeta expression and IL-15-driven proliferation. On the contrary, SEA enhances IL-15- and IL-2-induced proliferation via a CyA-sensitive pathway in this T-cell clone. In conclusion, the present data show that (i) SEA selectively inhibits IL-15- (but not PMA-) mediated proliferation in SEA "responder" T cells, (ii) SEA enhances cytokine-driven growth in psoriasis T cells with a "non-responder" phenotype, and (iii) crosstalk between SEA receptors and the IL-15R (and IL-2R) pathway is mediated via a PP2B-dependent and PP1/PP2A-, PKC-, PI-3 kinase- and mTOR-independent pathway in human T-cell lines.
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PMID:Staphylococcus enterotoxin A modulates interleukin 15-induced signaling and mitogenesis in human T cells. 951 Mar 72

Mast cells play an important role in the pathological development of many inflammatory and allergic diseases and inhibition of mast cell activation is a potential target for therapeutic intervention. Therefore, the effect of the novel ascomycin macrolactam derivative SDZ ASM 981 on Fc epsilonRI-mediated activation of rat basophilic leukemia (RBL) cells, as a model for mast cell activation, was investigated. First, the ability to inhibit different mast cell immunophilins in vitro was tested. Using recombinant macrophilin-12 (FKBP-12), inhibition of rotamase activity with an IC50 of approximately 6 nM was observed. The rotamase activity of cyclophilin A (18 kDa) was not affected. Secondly, the effect of SDZ ASM 981 on Fc epsilonRI-mediated mast cell activation was investigated in the RBL cell model. SDZ ASM 981 inhibited exocytosis of preformed mediators (e.g. serotonin) with an IC50 of approximately 30 nM. Transcription and release of newly synthesized mediators (e.g. TNF-alpha) was inhibited with an IC50 of approximately 100 nM. The inhibitory effect of SDZ ASM 981 was antagonized by rapamycin. We conclude that SDZ ASM 981 is a potent inhibitor of Fc epsilonRI-mediated activation of mast cells in vitro. The mechanism of action involves formation of (calcineurin) inhibitory complexes with macrophilins. We suggest that this inhibitory action on mast cells might contribute to the antiinflammatory effect of SDZ ASM 981 observed in vivo (e.g. in aptopic dermatitis and psoriasis).
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PMID:Ascomycin macrolactam derivative SDZ ASM 981 inhibits the release of granule-associated mediators and of newly synthesized cytokines in RBL 2H3 mast cells in an immunophilin-dependent manner. 980 44

Psoriasis is recognized as the most common T cell-mediated inflammatory disease in humans. Genetic linkage to as many as six distinct disease loci has been established but the molecular etiology and genetics remain unknown. To begin to identify psoriasis disease-related genes and construct in vivo pathways of the inflammatory process, a genome-wide expression screen of multiple psoriasis patients was undertaken. A comprehensive list of 159 genes that define psoriasis in molecular terms was generated; numerous genes in this set mapped to six different disease-associated loci. To further interpret the functional role of this gene set in the disease process, a longitudinal pharmacogenomic study was initiated to understand how expression levels of these transcripts are altered following patient treatment with therapeutic agents that antagonize calcineurin or NF-KB pathways. Transcript levels for a subset of these 159 genes changed significantly in those patients who responded to therapy and many of the changes preceded clinical improvement. The disease-related gene map provides new insights into the pathogenesis of psoriasis, wound healing and cellular-immune reactions occurring in human skin as well as other T cell-mediated autoimmune diseases. In addition, it provides a set of candidate genes that may serve as novel therapeutic intervention points as well as surrogate and predictive markers of treatment outcome.
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PMID:Molecular classification of psoriasis disease-associated genes through pharmacogenomic expression profiling. 1191 Nov 24

Systemic cyclosporin A and tacrolimus are effective treatments for psoriasis. Cyclosporin A and tacrolimus block T cell activation by inhibiting the phosphatase calcineurin and preventing translocation from the cytoplasm to the nucleus of the transcription factor nuclear factor of activated T cells (NFAT). Inhibition of T cell activation is thought to account for their therapeutic action in psoriasis. We investigated whether nonimmune cells in human skin express calcineurin and NFAT1 and whether cyclosporin A and tacrolimus block activation of calcineurin/NFAT in epidermal keratinocytes. The expression patterns of the principal components of calcineurin/NFAT signaling pathway in normal human skin and psoriasis were determined by immunohistochemistry. We assessed calcineurin/NFAT activation in cultured keratinocytes by measuring the degree of nuclear localization of calcineurin and NFAT1 using immunofluorescence/confocal microscopy and assessed if cyclosporin A and tacrolimus blocked nuclear translocation of these proteins. A variety of cell types in normal and psoriatic skin expressed calcineurin and NFAT1, but expression was particularly prominent in keratinocytes. The principal cyclosporin A and tacrolimus binding proteins cyclophilin A and FKBP12 were also expressed by keratinocytes and nonimmune cells in skin. NFAT1 was predominantly nuclear in normal basal epidermal keratinocytes. Increased nuclear localization of NFAT1 was observed in suprabasal keratinocytes within lesional and to a lesser extent nonlesional psoriatic epidermis compared to normal skin (p = 0.001 and p = 0.03, respectively), suggesting increased activation of calcineurin in psoriatic epidermal keratinocytes. Agonists that induce keratinocyte differentiation, specifically 12-0-tetradecanoyl-phorbol-13-acetate (TPA) plus ionomycin, TPA, and raised extracellular calcium, induced nuclear translocation of NFAT1 and calcineurin in keratinocytes that was inhibited by pretreatment with cyclosporin A or tacrolimus. In contrast in human dermal fibroblasts, TPA plus ionomycin or TPA did not significantly alter the proportion of nuclear-associated NFAT1. These data provide the first evidence that calcineurin is functionally active in human keratinocytes inducing nuclear translocation of NFAT1 and also indicate that regulation of NFAT1 nuclear translocation in skin is cell type specific. Inhibition of this pathway in epidermal keratinocytes may account, in part, for the therapeutic effect of cyclosporin A and tacrolimus in skin diseases such as psoriasis.
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PMID:Localization of calcineurin/NFAT in human skin and psoriasis and inhibition of calcineurin/NFAT activation in human keratinocytes by cyclosporin A. 1198 54

Macrolides are xenobiotics, produced by soil fungi, which have immunosuppressant properties. They will probably revolutionise the treatment of inflammatory dermatoses. This article outlines the context and putative mechanisms of action of this novel class of drugs. Cyclosporin, and the structurally distinct macrolides tacrolimus and pimecrolimus (an ascomycin derivative), modulate immune-cell function by inhibiting calcineurin-dependent dephosphorylation-activation of specific nuclear factors, thus preventing transcription of pro-inflammatory cytokines. The macrolide rapamycin (sirolimus) acts by abrogating Target of Rapamycin, a key signalling protein that controls activation of a number of proteins which direct progression of the cell cycle in response to pro-inflammatory cytokines. Tacrolimus and pimecrolimus are small enough molecules to penetrate skin and are available in topical formulations. "Skin-specific" pimecrolimus seems not to cause systemic immunosuppression when given orally. Neither topical tacrolimus nor pimecrolimus are capable of producing skin atrophy. Sirolimus has anti-angiogenic properties that may be beneficial to the treatment of psoriasis and perhaps skin cancer.
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PMID:The macrolide immunosuppressants in dermatology: mechanisms of action. 1245 45

Controlled trials and clinical experience indicate that systemic cyclosporin A and tacrolimus are effective treatments for psoriasis, and that cyclosporin A also improves atopic eczema. A variety of other inflammatory and non-inflammatory skin diseases are probably also responsive to these drugs. However, the widespread and longer-term use of cyclosporin A and tacrolimus are limited by side effects. The molecular mechanisms of action of cyclosporin A, tacrolimus and a related drug, sirolimus, have been well defined in T cells and involve inhibition of critical signalling pathways that regulate T cell activation. For example cyclosporin and tacrolimus inhibit calcineurin phosphatase activity and thereby inhibit activation of the transcription factor NFAT. The therapeutic efficacy of topical calcineurin inhibitors in atopic eczema have restimulated interest in the mechanism of action of these drugs in skin disease. Recently the expression pattern of calcineurin and NFAT has been defined in non-immune tissues including the akin. The relevance of this to the mechanism of action of systemic and topical calcineurin inhibitors and sirolimus in skin disorders is discussed.
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PMID:Calcineurin inhibitors and sirolimus: mechanisms of action and applications in dermatology. 1246 50

The development of topical calcineurin inhibitors resulted in a significant improvement in the treatment of inflammatory skin diseases such as atopic dermatitis. In addition, an excellent amelioration of pruritus could be observed. Other itchy dermatoses such as chronic irritative hand dermatitis, rosacea, graft-versus-host-disease, renal pruritus, lichen sclerosus, prurigo simplex, prurigo nodularis, scrotal eczema, and inverse psoriasis also have been treated successfully with pimecrolimus and tacrolimus. The antipruritic effect currently is believed to be related to the inhibition of inflammatory cytokines. Furthermore, recent investigations indicate a release of neuropeptides from sensory nerve fibers and degranulation of mast cells mediated by pimecrolimus and tacrolimus. Similar effects have been observed during capsaicin treatment. These findings may provide a possible explanation for initially observed calcineurin inhibitors related side-effects such as burning and pruritus. Moreover, the antipruritic potency may be related to a direct effect on nerve fibers leading to suppression of itch mediated by unknown mechanisms.
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PMID:[Antipruritic effects of pimecrolimus and tacrolimus]. 1271 60

Pimecrolimus (SDZ ASM 981), an ascomycin derivative, is one of the new classes of immunomodulating macrolactams and was specifically developed for the treatment of inflammatory skin diseases. The interest in pimecrolimus has been substantial because of its significant anti-inflammatory activity and immunomodulatory capabilities and its low systemic immunosuppressive potential. The mechanism of action of pimecrolimus is the blockage of T cell activation. Pimecrolimus (like all ascomycins) is an immunophilin ligand, which binds specifically to the cytosolic receptor, immunophilin macrophilin-12. This pimecrolimus-macrophilin complex effectively inhibits the protein phosphatase calcineurin, by preventing calcineurin from dephosphorylating the nuclear factor of activated T cells (NF-AT), a transcription factor. This results in the blockage of signal transduction pathways in T cells and the inhibition of the synthesis of inflammatory cytokines, specifically Th1- and Th2-type cytokines. Pimecrolimus has also been shown to prevent the release of cytokines and pro-inflammatory mediators from mast cells. Several studies have evaluated the effectiveness of pimecrolimus as a treatment for skin diseases. In animal models of allergic contact dermatitis, topical pimecrolimus was found to be effective. In human studies of allergic contact dermatitis pimecrolimus demonstrated significantly more efficacy than the control treatment. As well, the effectiveness of pimecrolimus 0.6% cream was comparable to 0.1% betamethasone-17-valerate; however, pimecrolimus was not associated with any of the side effects characteristic of a topical steroid. Topical application of pimecrolimus is not associated with skin atrophy. Pimecrolimus is effective and safe in both children and adults with atopic dermatitis. When pimecrolimus 1% cream has been applied to adult atopics, improvement has been observed as early as the first week, with a 72% reduction in severity after 3 weeks. Pharmacokinetic studies have shown very low blood levels of pimecrolimus following topical application, with no accumulation after repeated applications. Following application of pimecrolimus cream occasional transient irritation may be experienced at the application site. Similar results have also been found in children aged 3 months and older following application of pimecrolimus 1% cream. Topical pimecrolimus in psoriasis appears to exhibit a dose-dependent therapeutic effect under semi-occlusive conditions. Pimecrolimus has an enormous potential as a new treatment of inflammatory skin diseases. It has been shown to be effective in atopic and allergic contact dermatitis, with a favorable adverse-effects profile, which includes little effect on the systemic immune response.
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PMID:Pimecrolimus: a review. 1294 Oct 81


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