Differential regulation of interleukin-1 beta-induced cyclooxygenase-2 gene expression by nimesulide in human synovial fibroblasts.
Osteoarthritic (OA) human synovial fibroblasts (HSF) in culture were treated with the preferential COX-2 inhibitors nimesulide or NS-398, the non-specific COX-1/COX-2 inhibitor naproxen, or dexamethasone, in the presence or absence of IL-1 beta or LPS. Nimesulide or NS-398 inhibited IL-1 beta-induced PGE2 production at all concentrations tested, and in addition they suppressed IL-1 beta-induced COX-2 mRNA expression and protein synthesis. These suppressive effects were most evident at therapeutic levels of the drugs. Mechanistic studies revealed that the drug-induced inhibition of COX-2 expression and synthesis was not promoter-based, but may be associated with the blockade of IL-1 beta-dependent calcium flux and increased cellular calcium levels.
Di Battista
J A
JA
Université de Montreal, and Unité de Recherche en Arthrose, Centre Hospitalier de l'Université de Montreal, Hôpital Notre-Dame, 1560 rue Sherbrooke est, Montréal, Québec, Canada H2L 4M1.
Fahmi
H
H
He
Y
Y
Zhang
M
M
Martel-Pelletier
J
J
Pelletier
J P
JP
D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000201:enzymology / Q000601:surgery; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins; D009288:Naproxen / Q000494:pharmacology; D009578:Nitrobenzenes / Q000494:pharmacology; D010003:Osteoarthritis / Q000188:drug therapy / Q000201:enzymology / Q000601:surgery; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D013449:Sulfonamides / Q000494:pharmacology*; D013583:Synovial Membrane / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007375:Interleukin-1; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009578:Nitrobenzenes; D012333:RNA, Messenger; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D009288:Naproxen; D003907:Dexamethasone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; C012655:nimesulide