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.
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ABSTRACT: Integrin alphaupsilonbeta6 plays a very important role in the progression of colon cancer cells and is now defined as a novel, independent prognostic indicator for aggressive colon cancer in humans. Herein, we use the RNA interfering technology to downregulate the expression of alphaupsilonbeta6 in colon cancer cells. Our data demonstrate that plasmid vector based shRNA can effectively down-regulate alphaupsilonbeta6 expression in protein and mRNA levels. Supression of integrin alphaupsilonbeta6 inhibits the phosphorylation and nonphosphorylation level of ERK1/2, the secretion of uPA, pro-MMP-9 and pro-MMP-2 in tumor conditioned medium, and more important, inhibits MAPK-dependent [(3)H] labeled collagen IV degradation via the plasminogen activation cascade. Our study demonstrates in vitro that supression of integrin alphaupsilonbeta6 inhibits extracellular matrix degradation through the MAPK pathway.International Journal of Cancer 09/2008; 123(6):1311-1317. DOI:10.1002/ijc.23656 · 5.01 Impact Factor
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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.05/2012; 2012. DOI:10.5402/2012/182097
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ABSTRACT: Matrix metalloproteinases (MMPs) are a family of zinc-dependent enzymes capable of degradation of extracellular matrix (ECM) and key player in various inflammatory diseases. We investigated the regulation of MMPs in chronic gastric ulceration in mice. We generated chronic gastric ulcers in mice by indomethacin and examined the activity and expression of MMP-9 and -3 in stomach. Melatonin (N-acetyl-5-methoxytryptamine) treatment has also been applied to mice to characterize the changes in expression and activities of MMPs in gastric tissues. We observed significant upregulation of MMP-9 and -3 expressions and activities in stomach with increasing doses and duration of indomethacin that corroborated with increased activity of activator protein (AP)-1. Substantial damage in gastric epithelial layer was found during chronic ulceration. Melatonin suppressed MMP-9 and -3 expressions and activities during prevention and healing of chronic gastric ulcers. It also suppressed protein oxidation, lipid peroxidation and antioxidant enzymes. Additionally, expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-8 was significantly high in ulcerated stomachs while melatonin treatment blocked them to control level. We found elevated phosphorylation of extracellular-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK) during chronic gastric ulceration, which were significantly reversed by melatonin. Moreover, expression of NF-κB, c-fos and c-jun were inhibited by melatonin resulting down regulation of MMP-9 and -3 expressions. In summary, oxidative stress is preceded by chronic inflammation that enhances the expression of MMP-9 and -3, while melatonin arrests both of them via reduction of AP-1 activity during protection of ulcer.Biochimie 08/2012; 94(12). DOI:10.1016/j.biochi.2012.08.004 · 3.12 Impact Factor