TY - JOUR
T1 - Acetate inhibits NFAT activation in T cells via importin β1 interference
AU - Ishiguro, Kazuhiro
AU - Ando, Takafumi
AU - Maeda, Osamu
AU - Ohmiya, Naoki
AU - Niwa, Yasumasa
AU - Goto, Hidemi
PY - 2007/8
Y1 - 2007/8
N2 - 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-κB activation. Moreover, acetate impaired the nuclear translocation of NFAT but not that of NF-κB. Unlike cyclosporin A (CsA), acetate did not affect the dephosphorylation of NFAT and calcineurin activity. Acetate impaired the binding of NFAT to importin β1, 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 β1 in T cells and that acetate can potentially act as an anti-inflammatory agent.
AB - 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-κB activation. Moreover, acetate impaired the nuclear translocation of NFAT but not that of NF-κB. Unlike cyclosporin A (CsA), acetate did not affect the dephosphorylation of NFAT and calcineurin activity. Acetate impaired the binding of NFAT to importin β1, 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 β1 in T cells and that acetate can potentially act as an anti-inflammatory agent.
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U2 - 10.1002/eji.200737180
DO - 10.1002/eji.200737180
M3 - Article
C2 - 17615583
AN - SCOPUS:34547877600
SN - 0014-2980
VL - 37
SP - 2309
EP - 2316
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 8
ER -