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J. Biol. Chem., Vol. 282, Issue 17, 12804-12812, April 27, 2007

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Interleukin-6 Transcriptionally Regulates Prohibitin Expression in Intestinal Epithelial Cells^*

From the Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia 30322

Prohibitin (PHB) is a highly conserved protein that has multiple functions in the cell. We recently demonstrated that PHB plays an important role in combating oxidative stress and its expression is down-regulated in human and animal models of inflammatory bowel disease. Little is known regarding the regulation of PHB expression in intestine or other tissues. In this study we examined the regulation of PHB expression in intestinal epithelial cells using the model cell line Caco2-BBE. We successfully cloned the 1192-bp human PHB promoter region and identified the transcription start site 1594 bp upstream from the translation start site due to an intervening intron. We show that the acute phase cytokine interleukin-6 (IL-6) increases PHB protein and mRNA abundance and induces PHB promoter activation. The IL-6 response element site in the PHB promoter is required for maximal basal promoter activity and responsiveness to IL-6. IL-6 also increases binding of nuclear proteins to the IL-6 response element in the PHB promoter that are supershifted by a STAT3 antibody. Both basal promoter activity and IL-6 responsiveness are attenuated by signal transducer and activator of transcription 3 short interference RNA, suggesting that signal transducer and activator of transcription 3 mediates PHB activity by IL-6. Confirming these in vitro results, IL-6^-/- mice exhibit reduced PHB expression in the colon compared with wild-type mice. These results suggest that IL-6 modulates PHB expression in cultured intestinal epithelial cells and in the intestine in vivo.

Received for publication, September 22, 2006 , and in revised form, January 25, 2007.

The nucleotide sequence(s) reported in this paper has been submitted to the DDBJ/GenBank^TM/EBI Data Bank with accession number(s) DQ406856 [GenBank] .

^* This work was supported by a Ruth L. Kirschstein National Research Service Award for Individual Postdoctoral Fellow (F32-DK076243-01) (to A. L. T.), NIDDK, National Institutes of Health Grants RO1-DK06411 (to S. V. S.) and RO1-DK061941-02 (to D. M.) and Research Center Grant R24-DK064399. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Division of Digestive Diseases, Emory University, 615 Michael St., Whitehead Biomedical Research Bldg. 265, Atlanta, GA, 30322. Tel.: 404-712-2862; Fax: 404-727-5767; E-mail: atheiss{at}emory.edu.

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