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-kB-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/exportin-1alpha-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.

authors

Lindstedt R,Ruggiero V,D' Alessio V,Manganello S,Petronzelli F,Stasi MA,Vendetti S,Assandri A,Carminati P,De Santis R

doi

10.1177/039463200902200105

subject

Has Abstract

pub_date

2009-01-01 00:00:00

pages

29-42

issue

1

eissn

0394-6320

issn

2058-7384

pii

5

journal_volume

22

pub_type

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