Concordant induction of prostaglandin E2 synthase with cyclooxygenase-2 leads to preferred production of prostaglandin E2 over thromboxane and prostaglandin D2 in lipopolysaccharide-stimulated rat peritoneal macrophages.
Rat peritoneal macrophages were stimulated with lipopolysaccaride (LPS) for various periods and their ability to convert exogenous arachidonic acid to various prostanoids was examined. Unstimulated cells, which expressed cyclooxygenase (COX)-1 but not COX-2, produced thromboxane (TX) B2 > prostaglandin (PG) D2 > PGE2, whereas cells stimulated for 6-12 h with LPS exhibited marked increase in conversion to PGE2, which paralleled COX-2 induction, with minimal change in conversion to TXB2 and PGD2. Pharmacological studies showed that formation of PGE2 was mediated predominantly by COX-2, PGD2 by COX-1, and TXB2 by both COX-1 and COX-2 depending upon the timing of LPS stimulation. Measurement of the conversion of exogenous PGH2 to each prostanoid in cell lysates demonstrated LPS-dependent increase in PGE2 synthase activity that was degenerated by pretreatment with actinomycin D or cycloheximide. Thus, concordant induction of terminal PGE2 synthase with COX-2 leads to the preferred production of PGE2 to TXB2 and PGD2 by LPS-stimulated macrophages.
Matsumoto
H
H
Department of Pharmacology, School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo, Japan.
Naraba
H
H
Murakami
M
M
Kudo
I
I
Yamaki
K
K
Ueno
A
A
Oh-ishi
S
S
D000818:Animals; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D004790:Enzyme Induction; D007213:Indomethacin / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases; D007527:Isoenzymes / Q000096:biosynthesis*; D007535:Isomerases / Q000096:biosynthesis*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D008297:Male; D009578:Nitrobenzenes / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D013929:Thromboxane B2 / Q000378:metabolism*
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008070:Lipopolysaccharides; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D003609:Dactinomycin; D013929:Thromboxane B2; D003513:Cycloheximide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D007535:Isomerases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone; D015230:Prostaglandin D2; D007213:Indomethacin