Submitted on August 12, 2008
Revised on September 2, 2008
Accepted on September 17, 2008
INVOLVEMENT OF A STAT3 BINDING SITE IN INFLAMMATION-INDUCED ENTERIC APELIN EXPRESSION
Song Han1, Guiyun Wang1, Xiang Qi1, Ella W Englander1, and George H Greeley, Jr1*
1 University of Texas Medical Branch
* To whom correspondence should be addressed. E-mail: ggreeley{at}utmb.edu.
Apelin is the endogenous ligand for the APJ receptor, both are expressed in the gastrointestinal tract. Experimental colitis in rodents and inflammatory bowel disease in humans are associated with increased intestinal apelin production. Our aim was to use LPS and proinflammatory cytokine-treated (IL-6 and IFN-
) rodents or enteric cells to identify signaling mechanisms underlying inflammation-induced enteric apelin expression. LPS, IL-6 or IFN- treatment of rodents increased enteric apelin expression. Pharmacologic blockade of Jak/Stat signaling or IL-6 antibody administration inhibited elevations in enteric apelin expression. Transient transfection experiments showed that LPS, IL-6 or IFN- increased apelin expression by stimulation of apelin promoter activity, blockade of Jak/Stat signaling abolished elevations in apelin promoter activity. A ChIP assay showed that IL-6 induced binding of phospho-Stat3 to a putative Stat3 site in the apelin promoter, mutation of this site abrogated the LPS-induced elevation in apelin promoter activity. Together, our findings indicate that binding of phospho-Stat3 to the apelin promoter is the final step underlying proinflammatory cytokine-induced enteric apelin expression during intestinal inflammation.
