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Macrophage-Inflammatory Protein-3 Mediates Epidermal Growth Factor Receptor Transactivation and ERK1/2 MAPK Signaling in Caco-2 Colonic Epithelial Cells via Metalloproteinase-Dependent Release of Amphiregulin¹

Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215

Previously, we reported that normal colonocytes produce the memory CD4⁺ T cell-directed chemokine MIP-3, and that epithelial MIP-3 levels are elevated in inflammatory bowel disease. Interestingly, the unique receptor for MIP-3, CCR6, is expressed by a variety of cell types including colonocytes, suggesting that MIP-3 may regulate additional biological activities in the intestine. The aim of this study was to determine whether MIP-3 can induce intestinal epithelial cell proliferation and to examine the signaling mechanisms that mediate this response. We show that nonstimulated Caco-2 and HT-29 colonic epithelial cells express CCR6, and that stimulation of Caco-2 cells by MIP-3 can dose dependently increase cell proliferation as well as activate the epidermal growth factor receptor (EGFR) and ERK1/2 MAPK. MIP-3-mediated ERK1/2 activation in Caco-2 cells appeared to require metalloproteinase-dependent release of the endogenous EGFR ligand amphiregulin and transactivation of the EGFR. Moreover, blockade of amphiregulin bioactivity using a neutralizing polyclonal Ab significantly reduced MIP-3-mediated, but not EGF-mediated Caco-2 cell proliferation. Taken together, our findings indicate that MIP-3 can regulate mitogenic signaling in colonic epithelial cells and thus may serve an important homeostatic function in the intestine by regulating tissue turnover and maintenance of the epithelium, in addition to its role in regulating leukocyte recruitment.

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 This work was supported by Grants DK075942, DK58858, AIO53069, and P01 DK033506 from the National Institutes of Health, by Grant DK43551 from the Massachusetts General Hospital/New England Regional Primate Research Center for the Study of Inflammatory Bowel Diseases, by a First Award from the Crohn’s and Colitis Foundation of America and the William and Shelby Modell Family Foundation (to A.C.K.), and by an American Gastroenterological Association/TAP Endowed Research Award in Acid Related Diseases (to S.K.).

² Address correspondence and reprint requests to Dr. Andrew C. Keates, Division of Gastroenterology, Dana 501, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. E-mail address: akeates{at}bidmc.harvard.edu

³ Abbreviations used in this paper: IBD, inflammatory bowel disease; EGF, epidermal growth factor; EGFR, EGF receptor; TACE, TNF- converting enzyme; TAPI, TNF- protease inhibitor.

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