Microsomal prostaglandin E synthase is regulated by proinflammatory cytokines and glucocorticoids in primary rheumatoid synovial cells

The selective induction of PGE(2) synthesis in inflammation suggests that a PGE synthase may be linked to an inducible pathway for PG synthesis. We ex amined the expression of the recently cloned inducible microsomal PGE synth ase (mPGES) in synoviocytes from patients with rheumatoid arthritis, its mo dulation by cytokines and dexamethasone, and its linkage to the inducible c yclooxygenase-2. Northern blot analysis showed that IL-1 beta or TNF-alpha treatment induces mPGES mRNA from very low levels at baseline to maximum le vels at 24 h. IL-1 beta -induced mPGES mRNA was inhibited by dexamethasone in a dose-dependent fashion. Western blot analysis demonstrated that mPGES protein was induced by IL-1 beta, and maximum expression was sustained for up to 72 h. There was a coordinated up-regulation of cyclooxygenase-2 prote in, although peak expression was earlier. Differential Western blot analysi s of the microsomal and the cytosolic fractions revealed that the induced e xpression of mPGES protein was limited to the microsomal fraction. The dete cted mPGES protein was catalytically functional as indicated by a Mold incr ease of PGES activity in synoviocytes following treatment with IL-1 beta; t his increased synthase activity was limited to the microsomal fraction. In summary, these data demonstrate an induction of mPGES in rheumatoid synovio cytes by proinflammatory cytokines. This novel pathway may be a target for therapeutic intervention for patients with arthritis. The Journal of Immuno logy, 2001.