The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes.
We report here that the bacterial lipopolysaccharide endotoxin induces human blood monocytes in a time- and dose-dependent manner to release prodigious amounts of prostaglandins with thromboxane A2, the major metabolite formed. Cells responded to as little as 1 ng/ml lipopolysaccharide to release prostaglandin E2 and thromboxane A2 with maximal stimulation at 10 micrograms/ml. Lipopolysaccharide was found to induce increased activity of cyclooxygenase enzyme without affecting the activities of phospholipase and thromboxane synthase or the formation of 5-lipoxygenase products (e.g. leukotriene B4). The glucocorticoid dexamethasone completely blocked the lipopolysaccharide-induced prostanoid release by inhibiting the activity of monocyte cyclooxygenase. Dexamethasone did not affect phospholipase and thromboxane synthase activities or leukotriene formation. Immunoprecipitation of [35S]methionine-labeled cyclooxygenase confirmed that the effect of lipopolysaccharide and dexamethasone on the monocyte prostanoid production could be attributed to an increase or decrease, respectively, in cellular cyclooxygenase de novo synthesis.
Fu
J Y
JY
Department of Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110.
Masferrer
J L
JL
Seibert
K
K
Raz
A
A
Needleman
P
P
D001094:Arachidonate 5-Lipoxygenase / Q000097:blood; D000001:Calcimycin / Q000494:pharmacology; D002469:Cell Separation; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction; D006801:Humans; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008715:Methionine / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010740:Phospholipases / Q000097:blood; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000097:blood*
D008070:Lipopolysaccharides; D000001:Calcimycin; D003907:Dexamethasone; D008715:Methionine; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D010740:Phospholipases