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 examined the expression of the recently cloned inducible microsomal PGE synthase (mPGES) in synoviocytes from patients with rheumatoid arthritis, its modulation by cytokines and dexamethasone, and its linkage to the inducible cyclooxygenase-2. Northern blot analysis showed that IL-1beta or TNF-alpha treatment induces mPGES mRNA from very low levels at baseline to maximum levels at 24 h. IL-1beta-induced mPGES mRNA was inhibited by dexamethasone in a dose-dependent fashion. Western blot analysis demonstrated that mPGES protein was induced by IL-1beta, and maximum expression was sustained for up to 72 h. There was a coordinated up-regulation of cyclooxygenase-2 protein, although peak expression was earlier. Differential Western blot analysis of the microsomal and the cytosolic fractions revealed that the induced expression of mPGES protein was limited to the microsomal fraction. The detected mPGES protein was catalytically functional as indicated by a 3-fold increase of PGES activity in synoviocytes following treatment with IL-1beta; this increased synthase activity was limited to the microsomal fraction. In summary, these data demonstrate an induction of mPGES in rheumatoid synoviocytes by proinflammatory cytokines. This novel pathway may be a target for therapeutic intervention for patients with arthritis.
Stichtenoth
D O
DO
Divisions of. Rheumatology and Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Thorén
S
S
Bian
H
H
Peters-Golden
M
M
Jakobsson
P J
PJ
Crofford
L J
LJ
D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000502:physiology*; D003600:Cytosol / Q000201:enzymology; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D004789:Enzyme Activation / Q000276:immunology; D004790:Enzyme Induction / Q000235:genetics / Q000276:immunology; D005938:Glucocorticoids / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology*; D007375:Interleukin-1 / Q000502:physiology; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins; D008861:Microsomes / Q000201:enzymology*; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D013583:Synovial Membrane / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D016207:Cytokines; D005938:Glucocorticoids; D018836:Inflammation Mediators; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D003907:Dexamethasone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone