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Am J Physiol Gastrointest Liver Physiol 295: G1068-G1078, 2008. First published September 25, 2008; doi:10.1152/ajpgi.90493.2008
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INFLAMMATION/IMMUNITY/MEDIATORS

Involvement of a Stat3 binding site in inflammation-induced enteric apelin expression

Song Han, Guiyun Wang, Xiang Qi, Ella W. Englander, and George H. Greeley, Jr.

Department of Surgery, University of Texas Medical Branch, Galveston, Texas

Submitted 12 August 2008 ; accepted in final form 17 September 2008

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-{gamma}) rodents or enteric cells to identify signaling mechanisms underlying inflammation-induced enteric apelin expression. LPS, IL-6, or IFN-{gamma} treatment of rodents increased enteric apelin expression. Pharmacological 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-{gamma} increased apelin expression by stimulation of apelin promoter activity, and blockade of Jak/Stat signaling abolished elevations in apelin promoter activity. A chromatin immunoprecipitation 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.

rodent; gastrointestinal tract; lipopolysaccharide


Address for reprint requests and other correspondence: G. H. Greeley, Jr., Dept. of Surgery, Univ. of Texas Medical Branch, 301 Univ. Blvd., Galveston, TX 77555 (e-mail: ggreeley{at}UTMB.edu)






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