Matrix Metalloproteinase Secretion by Gastric Epithelial Cells Is Regulated by E Prostaglandins and MAPKs
Department of Medicine, New York University School of Medicine, New York, New York 10016, USA. Journal of Biological Chemistry
(Impact Factor: 4.57).
04/2005; 280(11):9973-9. DOI: 10.1074/jbc.M413522200
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.
Available from: Abdullah Kucukalp
- "In recent years, it has been shown that statins as lipidlowering medication and tetracycline as an antimicrobial agent may have anti-inflammatory and immunomodulator pleiotropic effects on various patient groups and more particularly on different connective tissues [9, 14, 28–30]. Statins have been reported to block MMP expression from vascular smooth muscles by Luan et al. , from carotid plaques by Molloy et al. , and from gastric epithelial cells by Pillinger et al. . It was determined by Takemoto and Liao  "
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ABSTRACT: Objectives. To compare the effects of intra-articular application of statin and tetracyclines on cartilage and synovial tissue on experimental osteoarthritis.
Methods. Osteoarthritis was created in 30 rabbits of 3 groups. The control group received saline intra-articularly, statin group, atorvastatin and the tetracycline group, doxycycline once a week for 3 weeks. Chondral and synovial tissues were evaluated macroscopically and histopathologically.
Results. Macroscopic evaluation determined mean values of control group 3.0, statin group 0.56, and tetracycline group 2.5. Histopathological evaluations determined mean values; femoral medial condyle cartilage tissue, control group, 14.60±1.00, statin group 2.20±1.30, tetracycline group 12.7±5.39: tibia medial plateau, control group, 14.33±8.68, statin group 2.89±1.96, tetracycline group, 15.90±7.03: synovial tissue, control group 12.22±3.63, statin group 4.33±2.69, tetracycline group 10.70±2.62. Average values of synovial tissue cell layer thickness were control group 14.46±2.35 μm, statin group 10.56±1.01 μm, tetracycline group 12.80±0.79 μm. All measurements showed statistically significant differences between statin and control groups (𝑃<0.05) but not between tetracycline and control groups (𝑃>0.05).
Conclusions. Tetracycline has little effect due to chemical modification requirement, and the effect is dose dependent. Statins have chondroprotective effects, so may become a novel therapeutic agent in osteoarthritis management after chemical processing.
Available from: Asish Kumar Mukhopadhyay
- "Several studies have demonstrated that Hp-infection induces the secretion of matrix metalloproteinases (MMPs) from a variety of gastric cells in vivo as well as in cultured cells, which in turn contribute to the pathogenesis of gastric ulcer and gastric cancer –. Gastric epithelial cells appear to be the major source of MMPs in Hp infected gastric tissues . MMPs are a family of diverse zinc dependant endopeptidases that have broad substrate specificity and play a crucial role in various physiological processes including tissue remodeling, organ development, wound repair and inflammatory processes –. "
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ABSTRACT: Current therapy-regimens against Helicobacter pylori (Hp) infections have considerable failure rates and adverse side effects that urge the quest for an effective alternative therapy. We have shown that curcumin is capable of eradicating Hp-infection in mice. Here we examine the mechanism by which curcumin protects Hp infection in cultured cells and mice. Since, MMP-3 and -9 are inflammatory molecules associated to the pathogenesis of Hp-infection, we investigated the role of curcumin on inflammatory MMPs as well as proinflammatory molecules. Curcumin dose dependently suppressed MMP-3 and -9 expression in Hp infected human gastric epithelial (AGS) cells. Consistently, Hp-eradication by curcumin-therapy involved significant downregulation of MMP-3 and -9 activities and expression in both cytotoxic associated gene (cag)(+ve) and cag(-ve) Hp-infected mouse gastric tissues. Moreover, we demonstrate that the conventional triple therapy (TT) alleviated MMP-3 and -9 activities less efficiently than curcumin and curcumin's action on MMPs was linked to decreased pro-inflammatory molecules and activator protein-1 activation in Hp-infected gastric tissues. Although both curcumin and TT were associated with MMP-3 and -9 downregulation during Hp-eradication, but unlike TT, curcumin enhanced peroxisome proliferator-activated receptor-γ and inhibitor of kappa B-α. These data indicate that curcumin-mediated healing of Hp-infection involves regulation of MMP-3 and -9 activities.
Available from: onlinelibrary.wiley.com
- "These adaptors in turn recruit Ras to the cell surface, resulting in the sequential activation of Raf, MEK1, and ERK1/2. EGF activation of the ERK pathway can activate multiple MMP genes simultaneously, including MMP-1 (Pillinger et al., 2005), MMP-3 (Kajanne et al., 2007), MMP-7, MMP-9 (McCawley et al., 1999) and MMP-14 (Kheradmand et al., 2002), as well as a host of other genes. The EGF receptor (EGFR) is constitutively activated in many cancers including breast and lung carcinomas. "
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ABSTRACT: An abundance of literature over the past several years indicates a growing interest in the role of matrix metalloproteinases (MMPs) in normal physiology and in disease pathology. MMPs were originally defined by their ability to degrade the extracellular matrix, but it is now well documented that their substrates extend far beyond matrix components. Recent reviews discuss the structure and function of the MMP family members, as well as the promoter sequences that control gene expression. Thus, we focus on the signal transduction pathways that confer differential cell-type expression of MMPs, as well as on some novel non-matrix degrading functions of MMPs, particularly their intracellular location where they may contribute to apoptosis. In addition, increasing data implicate MMPs as "good guys", protective agents in some cancers and in helping to resolve acute pathologic conditions. Despite the intricate and complicated roles of MMPs in physiology and pathology, the goal of designing therapeutics that can selectively target MMPs remains a major focus. Developing MMP inhibitors with targeted specificity will be difficult; success will depend on understanding the role of these enzymes in homeostasis and on the careful delineation of mechanisms by which this family of enzymes mediates disease pathology.
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