c-Fos is a critical mediator of inflammatory-mediated repression of the apical sodium-dependent bile acid transporter.
BACKGROUND & AIMS: Ileal bile acid malabsorption is present in Crohn's ileitis. The molecular mechanisms of regulation of the apical sodium-dependent bile acid transporter ( ASBT) by inflammatory cytokines in vitro and in vivo are investigated. METHODS: Transient transfection studies of the human, mouse, and rat ASBT promoters and Northern analyses were performed in cells treated with the inflammatory cytokines and/or various activator protein-1 constructs. Rat ASBT promoter transgenic, wild-type, and c-fos-null mice were treated with indomethacin to assess the response to acute inflammation of the ileal mucosa. RESULTS: In Caco-2 cells, ASBT messenger RNA expression was reduced 65% after interleukin-1beta treatment, while c-fos and c-jun were up-regulated 2-fold. Human ASBT promoter activity was enhanced by c-jun and repressed by a dominant negative c-jun, c-fos, or a dominant negative c-fos. Meanwhile, c-fos antisense treatment activated the human ASBT promoter 5-fold and not only abrogated interleukin-1beta- mediated repression but led to a paradoxical increase in ASBT promoter activity. Indomethacin-induced acute ileitis led to repression of ASBT in wild-type mice and in the transgenic rat ASBT promoter reporter, while paradoxical activation of ASBT was seen in c-fos-null mice. Indomethacin-induced ileal injury was greater in the c-fos-null mice compared with the wild-type littermates. CONCLUSIONS: Human, rat, and mouse ASBT is inhibited by inflammatory cytokines via direct interactions of c-fos with the ASBT promoter.[1]References
- c-Fos is a critical mediator of inflammatory-mediated repression of the apical sodium-dependent bile acid transporter. Neimark, E., Chen, F., Li, X., Magid, M.S., Alasio, T.M., Frankenberg, T., Sinha, J., Dawson, P.A., Shneider, B.L. Gastroenterology (2006) [Pubmed]
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