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J. Biol. Chem., Vol. 282, Issue 9, 6242-6254, March 2, 2007

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Functional and Intracellular Signaling Differences Associated with the Helicobacter pylori AlpAB Adhesin from Western and East Asian Strains^*

Hong Lu, Jeng Yih Wu^¶, Ellen J. Beswick^||, Tomoyuki Ohno, Stefan Odenbreit^**, Rainer Haas^**, Victor E. Reyes^||, Masakazu Kita, David Y. Graham, and Yoshio Yamaoka¹

From the Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas 77030, the Department of Gastroenterology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Disease, Shanghai 200001, China, the ^¶Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, the Departments of ^||Pediatrics and Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555, the ^**Max von Pettenkofer Institute for Hygiene and Medical Microbiology, Ludwig Maximilians University, Munich D-80336, Germany, and the Department of Microbiology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan

Following adhesion of Helicobacter pylori to gastric epithelial cells, intracellular signaling leads to cytokine production, which causes H. pylori-related gastric injury. Two adjacent homologous genes (alpA and alpB), which encode H. pylori outer membrane proteins, are thought to be associated with adhesion and cytokine induction. We co-cultured gastric epithelial cells with wild type H. pylori strains and their corresponding alpA/alpB-deleted mutants (alpAB). Results were confirmed by complementation. Flow cytometry confirmed that AlpAB was involved in cellular adhesion. Deletion of alpAB reduced interleukin (IL)-6 induction in gastric epithelial cells. Deletion of alpAB reduced IL-8 induction with East Asian but not with Western strains. All AlpAB-positive strains tested activated the extracellular signal-regulated kinase, c-Fos, and cAMP-responsive element-binding protein. Activation of the Jun-N-terminal kinase, c-Jun, and NF-B was exclusive to AlpAB from East Asian strains. alpAB mutants poorly colonized the stomachs of C57BL/6 mice and were associated with lower mucosal levels of KC and IL-6. Our results suggest that AlpAB may induce gastric injury by mediating adherence to gastric epithelial cells and by modulating proinflammatory intracellular signaling cascades. Known geographical differences in H. pylori-related clinical outcomes may relate to differential effects of East Asian and Western types of AlpAB on NF-B-related proinflammatory signaling pathways.

Received for publication, December 6, 2006 , and in revised form, December 26, 2006.

^* This work was supported by National Institutes of Health Grants DK62813 (to Y. Y.), DK50669 (to V. E. R.), and DK56338 (which funds the Texas Gulf Coast Digestive Diseases Center), the Veterans Affairs Merit Review Program (to D. Y. G.), and Deutsche Forschungsgemeinschaft Grant HA2697/9-1 (to R. H.). 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 nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AB271157 [GenBank] –AB271165 [GenBank] .

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S5.

¹ To whom correspondence should be addressed: Dept. of Medicine/Gastroenterology, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Blvd., Houston, TX 77030. Tel.: 713-794-7597; Fax: 713-795-4471; E-mail: yyamaoka{at}bcm.tmc.edu.

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