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J. Biol. Chem., Vol. 283, Issue 35, 23922-23930, August 29, 2008

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Regulation of the Helicobacter pylori Cellular Receptor Decay-accelerating Factor^*

Daniel P. O'Brien, Judith Romero-Gallo, Barbara G. Schneider, Rupesh Chaturvedi, Alberto Delgado, Elizabeth J. Harris^¶, Uma Krishna, Seth R. Ogden, Dawn A. Israel, Keith T. Wilson, and Richard M. Peek, Jr.^||1

From the Division of Gastroenterology, Department of Medicine, Department of Cancer Biology, and ^¶Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2279 and ^||Department of Veterans Affairs Medical Center, Nashville, Tennessee 37212

Chronic gastritis induced by Helicobacter pylori is the strongest known risk factor for peptic ulceration and distal gastric cancer, and adherence of H. pylori to gastric epithelial cells is critical for induction of inflammation. One H. pylori constituent that increases disease risk is the cag pathogenicity island, which encodes a secretion system that translocates bacterial effector molecules into host cells. Decay-accelerating factor (DAF) is a cellular receptor for H. pylori and a mediator of the inflammatory response to this pathogen. H. pylori induces DAF expression in human gastric epithelial cells; therefore, we sought to define the mechanism by which H. pylori up-regulates DAF and to extend these findings into a murine model of H. pylori-induced injury. Co-culture of MKN28 gastric epithelial cells with the wild-type H. pylori cag⁺ strain J166 induced transcriptional expression of DAF, which was attenuated by disruption of a structural component of the cag secretion system (cagE). H. pylori-induced expression of DAF was dependent upon activation of the p38 mitogen-activated protein kinase pathway but not NF-B. Hypergastrinemic INS-GAS mice infected with wild-type H. pylori demonstrated significantly increased DAF expression in gastric epithelium versus uninfected controls or mice infected with an H. pylori cagE^- isogenic mutant strain. These results indicate that H. pylori cag⁺ strains induce up-regulation of a cognate cellular receptor in vitro and in vivo in a cag-dependent manner, representing the first evidence of regulation of an H. pylori host receptor by the cag pathogenicity island.

Received for publication, February 12, 2008 , and in revised form, June 23, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants DK73902, DK58587, and DK7795 (to R. M. P.) and DK053620 (to K. T. W.). This work was also supported by Vanderbilt Digestive Diseases Research Center Grant DK058404 and by the Office of Medical Research, Department of Veterans Affairs (to K. T. W.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence should be addressed: Division of Gastroenterology, Vanderbilt University School of Medicine, 2215 Garland Ave., 1030C MRB IV, Nashville, TN 37232-2279. Tel.: 615-322-5200; Fax: 615-343-6229; E-mail: richard.peek{at}vanderbilt.edu.

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