Structurally-unrelated immunosuppressive drugs, cyclosporin A and FK506 (tacrolimus), that share a common intracellular target protein, calcineurin, display strong and similar efficacy in the cases of organ transplantation and other immunological diseases. However, prolonged use of these drugs in many chronic diseases is restricted due, at least in part, to their side effects. The pharmacological effects of cyclosporin A and FK506, represented by the suppression of T cell activation and proliferation, are exhibited via inhibiting the activity of a transcription factor, nuclear factors of activated T cells (NFAT). The NFAT family members are involved in inducible expression of numerous genes concerned with immune responses as well as other biological events. Studies using gene-targeted mice have suggested that each NFAT family member plays a differential role in the synthesis of multiple cytokines. The diversity of the NFAT family is one of the reasons for the potent and wide-variety of side effects induced by cyclosporin A and FK506. However, molecular mechanisms underlying the functional differences among the NFAT family have not been fully elucidated. We have been investigating the comparative roles of NFAT members in regulating T cell cytokine synthesis. In addition, in order to identify the essential region in NFAT responsible for the specificity of individual NFAT members, we have applied a novel assay technique to accurate assessment of interacting properties between NFAT and its binding partners. This article summarizes the potential and possibility of selective NFAT inhibitors in the treatment of immunological and inflammatory diseases with introducing our recently elucidated findings.
Keywords: Calcineurin, cyclosporin A, cytokine, FK506, IL-2, NFAT, T cells, TNF-α
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