title: Acetate inhibits NFAT activation in T cells via importin beta1 interference.
abstract: Acetate is a principal short chain fatty acid produced by bacterial fermentation in the colon and a major end product of alcohol metabolism. In the present study, we assessed the effects of acetate on T cell activation and found that acetate inhibited NFAT activation but not NF-kappaB activation. Moreover, acetate impaired the nuclear translocation of NFAT but not that of NF-kappaB. Unlike cyclosporin A (CsA), acetate did not affect the dephosphorylation of NFAT and calcineurin activity. Acetate impaired the binding of NFAT to importin beta1, which is involved in NFAT nuclear translocation. NFAT is a critical transcription factor in cytokine and early response gene expression in activated T cells. Agents targeting NFAT such as CsA are used to suppress harmful immune responses in inflammatory diseases. Therefore, we also evaluated the efficacy of acetate in murine models of inflammatory diseases, and found that acetate administration (as well as administration of dexamethasone) attenuated trinitrobenzenesulfonic acid-induced colitis and dinitrofluorobenzene-induced dermatitis. These findings indicate for the first time that acetate inhibits NFAT activation by interfering with the interaction between NFAT and importin beta1 in T cells and that acetate can potentially act as an anti-inflammatory agent.
authors.affiliation: Molecular Biology and Pathogenesis of Gastroenterology, School of Medicine, Nagoya University, Nagoya, Japan. kio@med.nagoya-u.ac.jp
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ishiguro
authors.forename: Takafumi
authors.initials: T
authors.lastname: Ando
authors.forename: Osamu
authors.initials: O
authors.lastname: Maeda
authors.forename: Naoki
authors.initials: N
authors.lastname: Ohmiya
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Niwa
authors.forename: Hidemi
authors.initials: H
authors.lastname: Goto
mesh_terms: D019342:Acetic Acid / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy; D003872:Dermatitis / Q000188:drug therapy; D004139:Dinitrofluorobenzene / Q000633:toxicity; D004789:Enzyme Activation / Q000187:drug effects*; D005232:Fatty Acids, Volatile / Q000494:pharmacology; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D019169:Jurkat Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000187:drug effects* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D028961:beta Karyopherins / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D005232:Fatty Acids, Volatile; D007376:Interleukin-2; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D028961:beta Karyopherins; D014302:Trinitrobenzenesulfonic Acid; D004139:Dinitrofluorobenzene; D019342:Acetic Acid