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J. Biol. Chem., Vol. 282, Issue 26, 18722-18731, June 29, 2007

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Helicobacter pylori Stimulates Gastric Epithelial Cell MMP-1 Secretion via CagA-dependent and -independent ERK Activation^*

Michael H. Pillinger^¶12, Nada Marjanovic^¶1, Seok-Yong Kim^||, Yong-Chan Lee^**, Jose U. Scher^¶, Jatin Roper, Aryeh M. Abeles^¶, Peter I. Izmirly^¶, Matthew Axelrod^¶, Mara Y. Pillinger^¶, Sonia Tolani^¶, Victoria Dinsell^¶, Steven B. Abramson^¶, and Martin J. Blaser

From the Department of Medicine, New York University School of Medicine, New York, New York 10016, the Medical Service, New York Harbor Healthcare System, New York Campus of the Department of Veterans Affairs, New York, New York 10010, the ^¶Department of Rheumatology, Hospital for Joint Diseases, New York, New York 10003, the ^||Department of Microbiology, College of Medicine, Chungbuk National University, Cheongju 361-763, Korea, and the ^**Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea

Because the mechanisms of Helicobacter pylori-induced gastric injury are incompletely understood, we examined the hypothesis that H. pylori induces matrix metalloproteinase-1 (MMP-1) secretion, with potential to disrupt gastric stroma. We further tested the role of CagA, an H. pylori virulence factor, in MMP-1 secretion. Co-incubation of AGS cells with Tx30a, an H. pylori strain lacking the cagA virulence gene, stimulated MMP-1 secretion, confirming cagA-independent secretion. Co-incubation with strain 147C (cagA⁺) resulted in CagA translocation into AGS cells and increased MMP-1 secretion relative to Tx30a. Transfection of cells with the recombinant 147C cagA gene also induced MMP-1 secretion, indicating that CagA can independently stimulate MMP-1 secretion. Co-incubation with strain 147A, containing a cagA gene that lacks an EPIYA tyrosine phosphorylation motif, as well as transfection with 147A cagA, yielded an MMP-1 secretion intermediate between no treatment and 147C, indicating that CagA tyrosine phosphorylation regulates cellular signaling in this model system. H. pylori induced activation of the MAP kinase ERK, with CagA-independent (early) and dependent (later) components. MEK inhibitors UO126 and PD98059 inhibited both CagA-independent and -dependent MMP-1 secretion, whereas p38 inhibition enhanced MMP-1 secretion and ERK activation, suggesting p38 negative regulation of MMP-1 and ERK. These data indicate H. pylori effects on host epithelial MMP-1 expression via ERK, with p38 playing a potential regulatory role.

Received for publication, April 10, 2007

^* This work was supported by grants from the Arthritis Foundation New York Chapter and the American College of Rheumatology (to M. H. P.) and National Institutes of Health Grants RO1-AR47206-01 (to S. B. A.) and RO1 GM63270 (to M. J. B.). 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: 630-111J, New York Harbor Healthcare System, 423 East 23rd St., New York, NY 10010. Tel.: 212-951-3328; Fax: 212-951-3329; E-mail: michael.pillinger{at}med.nyu.edu.

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