Microsomal prostaglandin E synthase-1 is a major terminal synthase that is selectively up-regulated during cyclooxygenase-2-dependent prostaglandin E2 production in the rat adjuvant-induced arthritis model.
To better define the role of the various prostanoid synthases in the adjuvant-induced arthritis (AIA) model, we have determined the temporal expression of the inducible PGE synthase (mPGES-1), mPGES-2, the cytosolic PGES (cPGES/p23), and prostacyclin synthase, and compared with that of cyclooxygenase-1 (COX-1) and COX-2. The profile of induction of mPGES-1 (50- to 80-fold) in the primary paw was similar to that of COX-2 by both RNA and protein analysis. Quantitative PCR analysis indicated that induction of mPGES-1 at day 15 was within 2-fold that of COX-2. Increased PGES activity was measurable in membrane preparations of inflamed paws, and the activity was inhibitable by MK-886 to >or=90% with a potency similar to that of recombinant rat mPGES-1 (IC(50) = 2.4 microM). The RNA of the newly described mPGES-2 decreased by 2- to 3-fold in primary paws between days 1 and 15 postadjuvant. The cPGES/p23 and COX-1 were induced during AIA, but at much lower levels (2- to 6-fold) than mPGES-1, with the peak of cPGES/p23 expression occurring later than that of COX-2 and PGE(2) production. Prostacyclin (measured as 6-keto-PGF(1alpha)) was transiently elevated on day 1, and prostacyclin synthase was down-regulated at the RNA level after day 3, suggesting a diminished role of prostacyclin during the maintenance of chronic inflammation in the rat AIA. These results show that mPGES-1 is up-regulated throughout the development of AIA and suggest that it plays a major role in the elevated production of PGE(2) in this model.
Claveau
David
D
Department of Biochemistry, Merck Frosst Center for Therapeutic Research, Kirkland, Quebec, Canada.
Sirinyan
Mirna
M
Guay
Jocelyne
J
Gordon
Robert
R
Chan
Chi-Chung
CC
Bureau
Yves
Y
Riendeau
Denis
D
Mancini
Joseph A
JA
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage; D001169:Arthritis, Experimental / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D051546:Cyclooxygenase 2; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D015232:Dinoprostone / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D004487:Edema / Q000201:enzymology / Q000473:pathology; D011464:Epoprostenol / Q000096:biosynthesis / Q000235:genetics; D006614:Hindlimb; D007211:Indoles / Q000494:pharmacology; D007271:Injections, Intradermal; D007425:Intracellular Membranes / Q000187:drug effects / Q000201:enzymology; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology*; D009161:Mycobacterium / Q000276:immunology; D011448:Prostaglandin Antagonists / Q000096:biosynthesis / Q000494:pharmacology; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D002722:Chlorobenzenes
D000276:Adjuvants, Immunologic; D000942:Antigens, Bacterial; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D011464:Epoprostenol; D007211:Indoles; D019746:Intramolecular Oxidoreductases; D007527:Isoenzymes; D011448:Prostaglandin Antagonists; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases; D012333:RNA, Messenger; C060893:MK-886; D002722:Chlorobenzenes