Cyclooxygenase-2-Derived E Prostaglandins Down-Regulate Matrix Metalloproteinase-1 Expression in Fibroblast-Like Synoviocytes via Inhibition of Extracellular Signal-Regulated Kinase Activation
| Autor: | Paul F. Gomez, Pamela Rosenthal, Michael H. Pillinger, Victoria Dinsell, Steven B. Abramson, Sonia Tolani, Jeff Greenberg, Beth Apsel, Edwin S. L. Chan |
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| Rok vydání: | 2003 |
| Předmět: |
MAPK/ERK pathway
Extracellular signal-regulated kinases Immunology Down-Regulation Stimulation Matrix Metalloproteinase Inhibitors Matrix metalloproteinase medicine Extracellular Animals Humans Immunology and Allergy Enzyme Inhibitors Fibroblast Cells Cultured Aspirin biology Tumor Necrosis Factor-alpha Kinase Chemistry Prostaglandins E Anti-Inflammatory Agents Non-Steroidal Synovial Membrane Membrane Proteins Fibroblasts Up-Regulation Cell biology Enzyme Activation Isoenzymes medicine.anatomical_structure Biochemistry Cyclooxygenase 2 Prostaglandin-Endoperoxide Synthases biology.protein Rabbits Cyclooxygenase Matrix Metalloproteinase 1 Mitogen-Activated Protein Kinases Extracellular Space Interleukin-1 Signal Transduction |
| Zdroj: | The Journal of Immunology. 171:6080-6089 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.171.11.6080 |
| Popis: | We examined the regulation of matrix metalloproteinase (MMP) production by mitogen-activated protein kinases and cyclooxygenases (COXs) in fibroblast-like synoviocytes (FLSCs). IL-1β and TNF-α stimulated FLSC extracellular signal-regulated kinase (ERK) activation as well as MMP-1 and -13 release. Pharmacologic inhibitors of ERK inhibited MMP-1, but not MMP-13 expression. Whereas millimolar salicylates inhibited both ERK and MMP-1, nonsalicylate COX and selective COX-2 inhibitors enhanced stimulated MMP-1 release. Addition of exogenous PGE1 or PGE2 inhibited MMP-1, reversed the effects of COX inhibitors, and inhibited ERK activation, suggesting that COX-2 activity tonically inhibits MMP-1 production via ERK inhibition by E PGs. Exposure of FLSCs to nonselective COX and selective COX-2 inhibitors in the absence of stimulation resulted in up-regulation of MMP-1 expression in an ERK-dependent manner. Moreover, COX inhibition sufficient to reduce PGE levels increased ERK activity. Our data indicate that: 1) ERK activation mediates MMP-1 but not MMP-13 release from FLSCs, 2) COX-2-derived E PGs inhibit MMP-1 release from FLSCs via inhibition of ERK, and 3) COX inhibitors, by attenuating PGE inhibition of ERK, enhance the release of MMP-1 by FLSC. |
| Databáze: | OpenAIRE |
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