Endocrinology, Vol 119, 62-69, Copyright © 1986 by Endocrine Society

ARTICLES

Inhibition of prostaglandin synthesis by glucocorticoids in human endothelial cells

GD Lewis, WB Campbell and AR Johnson

The vasodilator prostaglandins (PGs), prostacyclin (PGI2) and PGE2, may contribute to the inflammatory response. Because glucocorticosteroids reduce inflammation, possibly through inhibition of arachidonic acid release, we examined the influence of dexamethasone on PG formation in cultures of human endothelial cells. Binding of [3H]dexamethasone by intact cells was competed by unlabeled steroids and was half-maximal at 1.2 X 10(-8) M. A cytosolic fraction complexed with [3H]dexamethasone and migrated on sucrose density gradient centrifugation with a sedimentation coefficient of 8S. 3H-steroid binding was diminished by unlabeled steroid. Histamine, bradykinin, and the ionophore, A23187, stimulated release of PGI2 and PGE2 to as much as 25 times basal release. Dexamethasone (10(-11) to 10(-7) M) reduced PG formation in cells that were stimulated by histamine, bradykinin, calcium ionophore, or mechanical agitation. The inhibitory effect required at least 4 h to develop, was maximal at 24 h, and persisted after the steroid was removed. Hydrocortisone and triamcinolone had similar effects but were less potent than dexamethasone. Testosterone and progesterone did not affect PG generation. Both arachidonic acid and PGH2 augmented formation of PGs but were not inhibited by dexamethasone. Cortisol-21- mesylate, an antagonist of glucocorticoid receptors, blocked the effects of dexamethasone on PG formation, as did treatment of the cells with cycloheximide. We conclude that glucocorticoids inhibit PG production in endothelial cells by interaction with specific steroid receptors. The steroid-mediated inhibitory effect occurs at the level of arachidonic acid release and depends upon protein synthesis.

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