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J. Biol. Chem., Vol. 282, Issue 45, 32965-32973, November 9, 2007

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Epithelial-derived Fibronectin Expression, Signaling, and Function in Intestinal Inflammation^*

Vasantha L. Kolachala, Rahul Bajaj, Lixin Wang, Yutao Yan, Jeff D. Ritzenthaler^¶, Andrew T. Gewirtz, Jesse Roman^¶, Didier Merlin, and Shanthi V. Sitaraman¹

From the Divisions of Digestive Diseases and ^¶Pulmonary and Critical Care Medicine, Department of Medicine, and Department of Pathology Emory University, Atlanta, Georgia 30322

Fibronectin (FN) is a multifunctional extracellular matrix protein that plays an important role in cell proliferation, adhesion, and migration. FN expression or its role in colitis is not known. The goal of this study is to characterize FN expression, regulation, and role during intestinal inflammation. Wild-type and transgenic mice expressing luciferase under the control of the human FN promoter, given water or 3% dextran sodium sulfate, were used as animal models of colitis. The Caco2-BBE model intestinal epithelial cell line was used for in vitro studies. FN protein is abundantly expressed by surface epithelial cells in the normal colon. Immunohistochemistry and luciferase assay in mice expressing the FN promoter linked to luciferase demonstrated that FN synthesis was up-regulated during colitis, during both the acute phase and the healing phase. In vitro experiments demonstrated that FN increased the expression of the FN integrin receptor 51 in a dose- and time-dependent manner. FN also induced the expression and activation of NF-B. Further, FN potentiated Caco2-BBE cell attachment and wound healing, which was inhibited by RGD peptide as well as NF-B inhibitors MG-132 and 1-pyrrolidinecarbodithioic acid, ammonium salt. In conclusion, FN is abundantly expressed and synthesized by colonic epithelial cells. FN is transcriptionally up-regulated in epithelial cells during both the dextran sodium sulfate-induced colitic and the recovery phase. FN enhances cell attachment and wound healing, which is dependent on binding to the integrin receptor and the NF-B signaling. Together our data show that epithelial-derived FN potentiates cell attachment and wound healing through epithelial-matrix interactions and that FN expression may have important implications for maintaining normal epithelial integrity as well as regulating epithelial response to injury during colitis.

Received for publication, May 29, 2007 , and in revised form, August 24, 2007.

^* This work was supported by a Ruth L. Kirstein National Research Service Award for individual postdoctoral fellow (F32) (to V. L. K.), NIDDK, National Institutes of Health Grants DK06411 (to S. V. S.) and DK02831 (to D. M.), 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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