The Immunosuppressor ST1959, a 3,5-Diaryl-S-Triazole Derivative, Inhibits T Cell Activation by Reducing NFAT Nuclear Residency

Abstract

3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole (ST1959) has shown therapeutic effects in several animal models of autoimmune diseases. In this study the effects of ST1959 were further investigated in a murine model of colitis. The evidence obtained indicates that the beneficial effects exerted by ST1959 rely upon a decreased local immunological response. The cellular effects of ST1959 were additionally investigated on human peripheral blood mononuclear cells and Jurkat T cells by measuring cytokine production, cell proliferation and activation of a set of transcription factors. ST1959 decreases human T cell proliferation and inhibits cytokine expression at the transcriptional level. Moreover, at doses inhibiting cytokine production, ST1959 blocks phorbol 12-myristate 13-acetate (PMA) and ionomycin-induced nuclear factor protein of activated T cell (NFAT1) activity, without impairing AP-1-and NF-κB-dependent transcription. Immunofluorescence data show that ST1959 inhibits the nuclear residency of NFAT1 in both Jurkat and human peripheral blood mononuclear cells activated with PMA/ionomycin. leptomycin B, an inhibitor of CRM1/exportinlα-dependent nuclear export, reverted the inhibitory effect of ST1959 on NFAT1 nuclear localization. This indicates that ST1959 may increase the nuclear export of NFAT1, downregulating NFAT1 activity via a mechanism different from that of cyclosporin A, since it does not affect NFAT phosporylation/dephosphorylation steps. These findings provide new insights into the molecular mechanisms underlying the immunomodulatory activity of ST1959.