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J. Biol. Chem., Vol. 280, Issue 11, 9973-9979, March 18, 2005

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Matrix Metalloproteinase Secretion by Gastric Epithelial Cells Is Regulated by E Prostaglandins and MAPKs^*

Michael H. Pillinger¶||**, Nada Marjanovic¶||, Seok-Yong Kim, Jose U. Scher¶, Peter Izmirly¶, Sonia Tolani¶, Victoria Dinsell¶, Yong-Chan Lee, Martin J. Blaser, and Steven B. Abramson¶

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

Because matrix metalloproteinases (MMPs) play roles in inflammatory tissue injury, we asked whether MMP secretion by gastric epithelial cells may contribute to gastric injury in response to signals involved in Helicobacter pylori-induced inflammation and/or cyclooxygenase inhibition. Tumor necrosis factor (TNF)-, interleukin (IL)-1, and epidermal growth factor (EGF) stimulated gastric cell MMP-1 secretion, indicating that MMP-1 secretion occurs in inflammatory as well as non-inflammatory situations. MMP-1 secretion required activation of the MAPK Erk and subsequent protein synthesis but was down-regulated by the alternate MAPK, p38. In contrast, secretion of MMP-13 was stimulated by TNF-/IL-1 but not EGF and was Erk-independent and mediated by p38. MMP-13 secretion was more rapid (peak, 6 h) than MMP-1 (peak 30 h) and only partly depended on protein synthesis, suggesting initial release of a pre-existing MMP-13 pool. Therefore, MMP-1 and MMP-13 secretion are differentially regulated by MAPKs. MMP-1 secretion was regulated by E prostaglandins (PGEs) in an Erk-dependent manner. PGEs enhanced Erk activation and MMP-1 secretion in response to EGF but inhibited Erk and MMP-1 when TNF- and IL-1 were the stimuli, indicating that the effects of PGEs on gastric cell responses are context-dependent. These data show that secretion of MMPs is differentially regulated by MAPKs and suggest mechanisms through which H. pylori infection and/or cyclooxygenase inhibition may induce epithelial cell signaling to contribute to gastric ulcerogenesis.

Received for publication, December 1, 2004

^* Supported by grants from the Arthritis Foundation New York Chapter (to M. H. P.) and by 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.

^|| Both authors contributed equally to this work.

^** To whom correspondence should be addressed: Dept. of Medicine 630-111J, New York Harbor Healthcare System, 423 E. 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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