Mechanism of glucocorticoid-induced inhibition of prostaglandin synthesis.
In order to study the mechanism of steroid-induced inhibition of prostaglandin (PG) secretion, we have used rat renomedullary interstitial cells grown in tissue culture as an in vitro model. These cells have been shown by radio-immunoassay to produce high amounts of prostaglandins, mainly PGE2 and PGF2 alpha. Using (3H) dexamethasone, we have demonstrated in our cultures the existence of glucocorticoid binding sites which exhibit all the characteristics of physiological glucocorticoid receptors. Comparison between the biological activity (i.e. the ability to inhibit PG secretion) of the various steroids tested (dexamethasone, corticosterone, aldosterone, progesterone and estradiol) and their affinities for the glucocorticoid binding sites reveals a striking correlation between these two parameters. Steroids which bind to the receptors also inhibit prostaglandin secretion whereas testosterone and estradiol, which have a very weak affinity for the glucocorticoid binding sites do not inhibit PG secretion. In addition, actinomycin D (0.1 microgram/ml) and cycloheximide (0.1 microgram/ml) are able to abolish the inhibitory effect of dexamethasone on PG secretion. Our results indicate that the action of corticosteroids on prostaglandin secretion, which is believed to be the basis of their anti-inflammatory properties, is mediated through receptor occupancy and requires RNA and protein synthesis.
D000818:Animals; D001667:Binding, Competitive; D002478:Cells, Cultured; D003609:Dactinomycin / Q000494:pharmacology; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology*; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D011453:Prostaglandins / Q000096:biosynthesis*; D011458:Prostaglandins E / Q000096:biosynthesis; D011460:Prostaglandins F / Q000096:biosynthesis; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*
D005938:Glucocorticoids; D011453:Prostaglandins; D011458:Prostaglandins E; D011460:Prostaglandins F; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D003609:Dactinomycin; D003907:Dexamethasone