Abstract
Objective
Microsomal prostaglandin E synthase 1 (mPGES‐1) is the final enzyme of the cascade that produces prostaglandin E~2~ (PGE~2~), a key actor in arthritis. To study mPGES‐1 synthesis in human cartilage and its regulation by interleukin‐1β (IL‐1β), we used human cartilage and an immortalized human chondrocyte cell line. Furthermore, we investigated the signaling pathways involved in mPGES‐1 expression.
Methods
We used real‐time quantitative reverse transcription–polymerase chain reaction, Northern blotting, and Western blotting to measure mPGES‐1 messenger RNA (mRNA) and protein expression in human chondrocytes. PGE~2~ production was measured by enzyme‐linked immunosorbent assay.
Results
Cartilage specimens from osteoarthritis (OA) patients contained far greater amounts of mPGES‐1 and cyclooxygenase 2 (COX‐2) mRNA than did normal cartilage. Incubation with IL‐1β markedly increased mPGES‐1 mRNA and protein in a dose‐dependent and time‐dependent manner, in parallel with an increase in PGE~2~ levels. Both PD98059, an ERK pathway inhibitor, and SB203580, a p38α/β MAPK inhibitor, abolished the increases in mPGES‐1 mRNA and protein in response to IL‐1β. The specific p38α MAPK inhibitor SC906 suppressed IL‐1β–induced COX‐2 expression but not IL‐1β–induced mPGES‐1 expression, suggesting preferential involvement of p38β MAPK in IL‐1β–induced mPGES‐1 expression.
Conclusion
This study is the first to show that mPGES‐1 is stimulated in human chondrocytes by the proinflammatory cytokine IL‐1β via activation of both ERK‐1/2 and p38 MAPK in an isoform‐specific manner. We postulate that mPGES‐1 may be a novel target for OA therapy.