Abstract
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)-alpha, interleukin (IL)-1beta, 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-alpha/IL-1beta but not EGF and was Erk-independent and mediated by p38. MMP-13 secretion was more rapid (peak, 6 h) than MMP-1 (peak > or =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-alpha and IL-1beta 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.
Highlights
Whereas peptic ulcer disease (PUD)1 affects millions of patients in the United States each year [1], gastric inflammation is even more prevalent and predisposes to both PUD and adenocarcinoma of the stomach [2]
Matrix metalloproteinases (MMPs)-1 and MMP-13 Secretion Stimulated by tumor necrosis factor (TNF)-␣, IL-1, and epidermal growth factor (EGF)—We first examined whether AGS cell stimulation could induce MMP-1 secretion
We considered whether MMP secretion from host cells might contribute to gastric tissue stromal destruction because MMPs have analogous roles in other inflammatory diseases such as rheumatoid arthritis [19, 20]
Summary
Vol 280, No 11, Issue of March 18, pp. 9973–9979, 2005 Printed in U.S.A. Matrix Metalloproteinase Secretion by Gastric Epithelial Cells Is Regulated by E Prostaglandins and MAPKs*. 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. PGEs inhibit fibroblast-like synoviocyte secretion of MMP-1 via inhibition of Erk [15, 20, 40] This model suggests that autodestruction of stromal tissue in response to inflammatory stimuli may be mediated by MMP production and regulated by MAPKs and prostaglandins.
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