c-Fos is a critical mediator of inflammatory-mediated repression of the apical sodium-dependent bile acid transporter.
OBJECTIVE
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.
Neimark
Ezequiel
E
Division of Pediatric Hepatology, Department of Pediatrics, Mount Sinai School of Medicine, New York, New York 10029, USA.
Chen
Frank
F
Li
Xiaoping
X
Magid
Margret S
MS
Alasio
Teresa M
TM
Frankenberg
Tamara
T
Sinha
Jyoti
J
Dawson
Paul A
PA
Shneider
Benjamin L
BL
D000818:Animals; D015152:Blotting, Northern; D018938:Caco-2 Cells / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007079:Ileitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000633:toxicity; D007375:Interleukin-1 / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D027981:Symporters / Q000235:genetics / Q000378:metabolism*
D007375:Interleukin-1; D008562:Membrane Glycoproteins; D029363:Organic Anion Transporters, Sodium-Dependent; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D027981:Symporters; C071908:sodium-bile acid cotransporter; D007213:Indomethacin