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 μg/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.