title: 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.affiliation: R and D Sigma-Tau S.p.A., Pomezia, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Lindstedt
authors.forename: V
authors.initials: V
authors.lastname: Ruggiero
authors.forename: V
authors.initials: V
authors.lastname: D' Alessio
authors.forename: S
authors.initials: S
authors.lastname: Manganello
authors.forename: F
authors.initials: F
authors.lastname: Petronzelli
authors.forename: M A
authors.initials: MA
authors.lastname: Stasi
authors.forename: S
authors.initials: S
authors.lastname: Vendetti
authors.forename: A
authors.initials: A
authors.lastname: Assandri
authors.forename: P
authors.initials: P
authors.lastname: Carminati
authors.forename: R
authors.initials: R
authors.lastname: De Santis
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010766:Phosphorylation; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014157:Transcription Factors / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D014157:Transcription Factors; D014230:Triazoles; C030266:3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole; D014302:Trinitrobenzenesulfonic Acid