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)-␣, 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 noninflammatory 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.

Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

“…Matrix metalloproteinases (MMPs) are neutral proteases that act extracellularly to digest collagen and other connective tissue molecules. MMP dysregulation plays a critical role in tissue destruction in rheumatoid arthritis (RA) (86,87) and in gastric ulceration (88) and atherogenic vascular damage (89,90). Statins have been reported to decrease production of MMPs 1, 3, and 9 in human macrophages and vascular smooth muscle cells (91), MMPs 1 and 9 in carotid plaques (85), and MMP-3 in IL-1␤-stimulated chondrocytes (92).…”

Helicobacter pylori Stimulates Gastric Epithelial Cell MMP-1 Secretion via CagA-dependent and -independent ERK Activation

“…The cultures were incubated for the indicated times at 37°C, and supernatants collected, concentrated, and analyzed, as described (23). Adherent cells were washed 3 times with cold phosphate-buffered saline, lysed (20 mM Tris, pH 7.4, 1 mM EGTA, 2 mM sodium vanadate, 25 mM sodium fluoride, 0.5% (v/v) Triton X-100, 2 mM phenylmethylsulfonyl fluoride, 10 5 kallikrein units/ml aprotinin, and 10 g/ml each of chymostatin, antipain, and pepstatin) for 20 min at 4°C, as described (36), and lysates collected and used directly or frozen for further study.…”

“…In response to H. pylori and gastrin, secretion of MMP-7 and MMP-9, respectively, may be regulated by ERK (26,43). In response to cytokines, ERK mediates, and p38 inhibits, gastric cell MMP-1 secretion (23). Because the primary connective tissue components of gastric stroma are proteins susceptible to MMP-1 degradation (29,44,45), MMP-1 secretion may be particularly relevant to the pathogenesis of gastric damage.…”

“…In rheumatoid arthritis, MMP secretion by synovial fibroblasts in response to cytokines contributes to cartilage and bone destruction (21,22). Similarly, pro-inflammatory cytokines, such as interleukin-1␤ and tumor necrosis factor-␣, stimulate gastric epithelial cells to synthesize and secrete MMPs (23). Moreover, exposure of gastric epithelial cells to H. pylori also results in MMP secretion, including MMP-3, -7, and -9 (24 -26).…”

Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain

“…Accumulating data has revealed that COX-2 expression is not limited to sites of inflammation (Ek et al, 2001). COX-2 and COX-2 derived prostanoids have been implicated in the biological processes of angiogenesis (Ben-Av et al, 1995), proliferation (Gately and Li, 2004), apoptosis (Gilroy et al, 2003), cell adhesion (Pillinger et al, 2005) and inflammatory resolution (Gilroy et al, 1999;Wallace and Devchand, 2005) through COX-2-dependent and independent mechanisms (Tegeder et al, 2001). Cancer prevention by tNSAIDs and coxibs is partially due to their modulation of alternative eicosanoid pathways, which are non-COX-2 effects (Rigas and Kashfi, 2005) not requiring the presence of COX-2 enzyme.…”