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J. Biol. Chem., Vol. 281, Issue 5, 2868-2875, February 3, 2006

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Helicobacter pylori Encoding the Pathogenicity Island Activates Matrix Metalloproteinase 1 in Gastric Epithelial Cells via JNK and ERK^*

Sabine Krueger¹, Tanja Hundertmark, Thomas Kalinski, Ulrich Peitz, Thomas Wex, Peter Malfertheiner, Michael Naumann^¶, and Albert Roessner

From the Institute of Pathology,Department of Gastroenterology, Hepatology and Infectious Diseases, and the^¶Institute of Experimental Internal Medicine, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany

Helicobacter pylori colonizes the human gastric epithelium and induces an inflammatory response that is a trigger for gastric carcinogenesis. Matrix metalloproteinases (MMPs) have recently been shown to be up-regulated in gastric epithelial cells infected with H. pylori and might contribute to the pathogenesis of peptic ulcer. The aim of this study was to extend the knowledge about the effect of H. pylori infection on MMP-1 expression by gastric epithelial cells, the kinetics of induction, the pathogenetic properties of the bacterium, and the intracellular signaling pathways required for MMP-1 up-regulation. Expression of MMP-1 was induced more than 10-fold by co-culture of AGS⁺cells with H. pylori strains carrying the pathogenicity island (PAI). H. pylori strains with mutations in the PAI and a defective type IV secretion system had no effect on MMP-1. Double immunofluorescence revealed strong MMP-1 staining in epithelial cells of gastric biopsies at sites of bacterial attachment. In vitro, MMP-1 is up-regulated by interleukin-1 and tumor necrosis factor-, but these regulatory mechanisms are not operating in H. pylori infection as shown by inhibitory antibodies. Specific inhibitors of JNK kinase and ERK1/2 kinase were found to suppress the H. pylori-induced MMP-1 expression and activity. AGS cells treated with antisense MMP-1 showed a significantly reduced potential to degrade reconstituted basement membrane. Our results suggest that in gastric epithelial cells, H. pylori up-regulates MMP-1 in a type IV secretion system-dependent manner via JNK and ERK1/2. Induction of MMP-1 is further implicated in complex processes induced by H. pylori, resulting in tissue degradation and remodeling of the gastric mucosa.

Received for publication, October 11, 2005 , and in revised form, November 23, 2005.

^* This work was supported by the NBL-3 program of the Bundesministerium für Forschung und Technik Grant NBL3/01ZZ0107/PP14. 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 To whom correspondence should be addressed. Tel.: 49-391-6715803; Fax: 49-391-67290123; sabine.krueger{at}medizin.uni-magdeburg.de.

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