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J. Biol. Chem., Vol. 282, Issue 11, 8219-8227, March 16, 2007

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Interleukin-6 Induces Keratin Expression in Intestinal Epithelial Cells

POTENTIAL ROLE OF KERATIN-8 IN INTERLEUKIN-6-INDUCED BARRIER FUNCTION ALTERATIONS^*

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

Keratin 8 (K8) and keratin-18 (K18) are the major intermediate filament proteins in the intestinal epithelia. The regulation and function of keratin in the intestinal epithelia is largely unknown. In this study we addressed the role and regulation of K8 and K18 expression by interleukin 6 (IL-6). Caco2-BBE cell line and IL-6 null mice were used to study the effect of IL-6 on keratin expression. Keratin expression was studied by Northern blot, Western blot, and confocal microscopy. Paracellular permeability was assessed by apical-to-basal transport of a fluorescein isothiocyanate dextran probe (FD-4). K8 was silenced using the small interfering RNA approach. IL-6 significantly up-regulated mRNA and protein levels of K8 and K18. Confocal microscopy showed a reticular pattern of intracellular keratin localized to the subapical region after IL-6 treatment. IL-6 also induced serine phosphorylation of K8. IL-6 decreased paracellular flux of FD-4 compared with vehicle-treated monolayers. K8 silencing abolished the decrease in paracellular permeability induced by IL-6. Administration of dextran sodium sulfate (DSS) significantly increased intestinal permeability in IL-6^-/- mice compared with wild type mice given DSS. Collectively, our data demonstrate that IL-6 regulates the colonic expression of K8 and K18, and K8/K18 mediates barrier protection by IL-6 under conditions where intestinal barrier is compromised. Thus, our data uncover a novel function of these abundant cytoskeletal proteins, which may have implications in intestinal disorders such as inflammatory bowel disease wherein barrier dysfunction underlies the inflammatory response.

Received for publication, April 28, 2006 , and in revised form, December 11, 2006.

^* This work was supported by NIDDK, National Institutes of Health Grant DK06411 and a Crohn's and Colitis Foundation of American Senior Award (to S. V. S.), NIDDK, National Institutes of Health Grants DK 02831 (to D. M.) and DK 067045 (to S. S.), and Digestive Disease Research Center Grant 5R24DK064399-02. 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, Rm. 201-F, 615, Michael St., Whitehead Research Bldg., Emory University, Atlanta, GA 30322. Tel.: 404-727-2430; Fax: 404-727-5767; E-mail: ssitar2{at}emory.edu.

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