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: R Lindstedt, V Ruggiero, V D' Alessio, S Manganello, F Petronzelli, M A Stasi, S Vendetti, A Assandri, P Carminati, R De Santis
• Journal: International journal of immunopathology and pharmacology (Int J Immunopathol Pharmacol) 2009 Jan-Mar Vol. 22 Issue 1 Pg. 29-42 ISSN: 0394-6320 [Print] England
• PMID: 19309550 (Publication Type: Journal Article)

Chemical References

• Cytokines
• Immunosuppressive Agents
• NFATC Transcription Factors
• Transcription Factors
• Triazoles
• 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole
• Trinitrobenzenesulfonic Acid

Topics

• Active Transport, Cell Nucleus (drug effects)
• Cell Nucleus (metabolism)
• Cytokines (biosynthesis, genetics)
• Humans
• Immunosuppressive Agents (pharmacology)
• Jurkat Cells
• Lymphocyte Activation (drug effects)
• NFATC Transcription Factors (metabolism)
• Phosphorylation
• T-Lymphocytes (drug effects, immunology)
• Transcription Factors (metabolism)
• Triazoles (pharmacology)
• Trinitrobenzenesulfonic Acid