Calcineurin inhibitors and sirolimus: mechanisms of action and applications in dermatology

Abstract

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.

Elucidating the Substrate Specificity and Condensation Domain Activity of FkbP, the FK520 Pipecolate-Incorporating Enzyme

“…Ni-NTA chromatography resin was purchased from Qiagen. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]Acetyl-CoA and Amplify were obtained from Amersham Biosciences. Sodium [ 32 P]pyrophosphate was purchased from Perkin-Elmer.…”

Molecular Diagnostics of Calcineurin-Related Pathologies

“…The therapeutic effectiveness of the Cn inhibitors (CnIs)-principally cyclosporin A (CsA) and tacrolimus-widely in use for the prevention of allograft rejection in transplantation patients (9 ) and for the treatment of inflammatory skin conditions (10,11 ) is based on their ability to suppress the immune system by inhibiting the synthesis of these proinflammatory and T cell-recruiting cytokines (12 ). Complexes of CsA and tacrolimus with carrier proteins known as "immunophilins" bind to Cn in such a man-ner that docking and dephosphorylation of NFAT is severely hampered (1 ).…”

Calcineurin inhibitors in the treatment of allergic dermatitis

“…Ao se ligar à calmodulina, inibe a síntese de calcineurina nos linfócitos, células dendríticas, basófilos e eosinófilos. As ações imunológicas que se seguem foram observadas em estudos experimentais e in vitro, evidenciando-se: nos linfócitos T, a redução da transcrição e síntese de IL-2, IL-3, IL-4, IL-5, GM-CSF (fator de estímulo ao crescimento de monócitos e granulócitos), fator de necrose tumoral e interferon gama 16,17 ; diminuição das células dendríticas, que atuam como apresentadoras de antígenos e auxiliam no desencadeamento da resposta inflamatória alérgica [16][17][18] ; diminuição da síntese de mediadores de mastócitos e basófilos produzidos pela via da calcineurina 19 ; diminuição da liberação de histamina por basófilos periféricos (estudos in vitro) 19 ; redução dos níveis de substância P e fator de crescimento neuronal produzido pelos queratinócitos, colaborando para a redução do prurido 20 .…”