The immunosuppressor st1959, a 3,5-diaryl-s-triazole derivative, inhibits T cell activation by reducing NFAT nuclear residency.
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.
Lindstedt
R
R
R and D Sigma-Tau S.p.A., Pomezia, Italy.
Ruggiero
V
V
D' Alessio
V
V
Manganello
S
S
Petronzelli
F
F
Stasi
M A
MA
Vendetti
S
S
Assandri
A
A
Carminati
P
P
De Santis
R
R
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
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