title: Matrix metalloproteinase secretion by gastric epithelial cells is regulated by E prostaglandins and MAPKs.
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.
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, New York 10016, USA. michael.pillinger@med.nyu.edu
authors.forename: Michael H
authors.initials: MH
authors.lastname: Pillinger
authors.forename: Nada
authors.initials: N
authors.lastname: Marjanovic
authors.forename: Seok-Yong
authors.initials: SY
authors.lastname: Kim
authors.forename: Jose U
authors.initials: JU
authors.lastname: Scher
authors.forename: Peter
authors.initials: P
authors.lastname: Izmirly
authors.forename: Sonia
authors.initials: S
authors.lastname: Tolani
authors.forename: Victoria
authors.initials: V
authors.lastname: Dinsell
authors.forename: Yong-Chan
authors.initials: YC
authors.lastname: Lee
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Blaser
authors.forename: Steven B
authors.initials: SB
authors.lastname: Abramson
mesh_terms: D045744:Cell Line, Tumor; D017364:Collagenases / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015536:Down-Regulation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000382:microbiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D016480:Helicobacter pylori / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D007375:Interleukin-1 / Q000378:metabolism; D007700:Kinetics; D020935:MAP Kinase Signaling System; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008954:Models, Biological; D011458:Prostaglandins E / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D013270:Stomach / Q000382:microbiology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D011458:Prostaglandins E; D011500:Protein Synthesis Inhibitors; D014409:Tumor Necrosis Factor-alpha; D004815:Epidermal Growth Factor; D003513:Cycloheximide; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D020781:Matrix Metalloproteinase 1