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J. Biol. Chem., Vol. 281, Issue 45, 34651-34662, November 10, 2006

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Cag Pathogenicity Island-independent Up-regulation of Matrix Metalloproteinases-9 and -2 Secretion and Expression in Mice by Helicobacter pylori Infection^*

Parag Kundu¹, Asish K. Mukhopadhyay, Rajashree Patra, Aditi Banerjee, Douglas E. Berg^¶, and Snehasikta Swarnakar²

From the Indian Institute of Chemical Biology, Kolkata 700032, India, the National Institute of Cholera and Enteric Diseases, Kolkata 700010, India, and the ^¶Department of Molecular Microbiology, Washington University Medical School, St. Louis, Missouri 63110

Helicobacter pylori cag pathogenicity island (PAI) is a major determinant of gastric injury via induction of several matrix metalloproteinases (MMPs). In the present study, we examined the influence of the cag PAI on gastric infection and MMP-9 production in mice and in cultured cells. A new mouse colonizing Indian H. pylori strain (AM1) that lacks the cag PAI was used to study the cag PAI importance in inflammation. Groups of C57BL/6 mice were inoculated separately with H. pylori strains AM1 and SS1 (cag⁺), gastric tissues were histologically examined, and bacterial colonization was scored by quantitative culture. Mice infected with either cag⁺ or cag^- H. pylori strains showed gastric inflammation and elevated MMP-3 production. Significant up-regulation of pro-MMP-9 secretion and gene expression in H. pylori infected gastric tissues indicate dispensability of cag PAI for increased pro-MMP-9 secretion and synthesis in mice. In agreement, cell culture studies revealed that both AM1 and SS1 were equipotent in pro-MMP-9 induction in human gastric epithelial cells. Both strains showed moderate increase in MMP-2 activity in vivo and in vitro. In addition, increased secretion of tumor necrosis factor (TNF)-, interleukin (IL)-1, and IL-6 induced pro-MMP-9 secretion and synthesis in AM1 or SS1 strain-infected mice suggesting elicitation of pro-inflammatory cytokines by both cag^- and cag⁺ genotype. Moreover, tissue inhibitors of metalloproteinase-1 expression were decreased with increase in pro-MMP-9 induction. These data show that H. pylori may act through different pathways other than cag PAI-mediated for gastric inflammation and contribute to up-regulation of MMP-9 via pro-inflammatory cytokines.

Received for publication, May 12, 2006 , and in revised form, July 19, 2006.

^* This work was supported in part by Grants GAP209 of Indian Council of Medical Research, New Delhi and JICA/NICED 054-1061-E-O of Japan International Cooperation Agency. 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 Recipient of a senior research fellowship, University Grants Commission, India.

² To whom correspondence should be addressed: Dept. of Physiology, Indian Institute of Chemical Biology, Jadavpur, Kolkata-700032, India. Tel.: 91-33-2473-3491 (ext. 159); Fax: 91-33-1473-5197; E-mail: snehasiktas{at}hotmail.com.

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