c-Fos is a critical mediator of inflammatory-mediated repression of the apical sodium-dependent bile acid transporter.

Abstract

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.

• Authors: Ezequiel Neimark, Frank Chen, Xiaoping Li, Margret S Magid, Teresa M Alasio, Tamara Frankenberg, Jyoti Sinha, Paul A Dawson, Benjamin L Shneider
• Journal: Gastroenterology (Gastroenterology) Vol. 131 Issue 2 Pg. 554-67 (Aug 2006) ISSN: 0016-5085 [Print] United States
• PMID: 16890608 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Interleukin-1
• Membrane Glycoproteins
• Organic Anion Transporters, Sodium-Dependent
• Proto-Oncogene Proteins c-fos
• RNA, Messenger
• Symporters
• sodium-bile acid cotransporter
• Indomethacin

Topics

• Animals
• Blotting, Northern
• Caco-2 Cells (metabolism, pathology)
• Cells, Cultured
• Gene Expression (drug effects)
• Humans
• Ileitis (chemically induced, metabolism, pathology)
• In Vitro Techniques
• Indomethacin (toxicity)
• Interleukin-1 (pharmacology)
• Intestinal Mucosa (metabolism, pathology)
• Membrane Glycoproteins (metabolism)
• Mice
• Mice, Knockout
• Organic Anion Transporters, Sodium-Dependent (genetics, metabolism)
• Proto-Oncogene Proteins c-fos (metabolism)
• RNA, Messenger (genetics)
• Rats
• Symporters (genetics, metabolism)