Two antiatherogenic effects of progesterone on human macrophages; Inhibition of cholesteryl ester synthesis and block of its enhancement by glucocorticoids

The effects of progesterone and estradiol on cholesteryl ester (CE) formati on by monocyte-derived human macrophages were examined. Formation was asses sed from incorporation of C-14-cholesterol during a 20-h incubation with ho rmone and from that of H-3-oleate (3 h) after hormone removal. Progesterone inhibited cholesterol into CE and decreased CE cellular levels. Inhibition : 1) was reversed by progesterone removal; 2) was independent of the proges terone receptor (not blocked by the receptor antagonist RU40555); and 3) ex hibited specific structural requirements; 11 alpha-OH-progesterone was inhi bitory, whereas its stereoisomer 11 beta-OH-progesterone was not. In contra st to progesterone, estradiol was ineffective. We had reported that dexamet hasone enhanced CE accumulation by human macrophages (1). In this study, we describe similar effects of the endogenous steroid, cortisol, and of the m ost widely prescribed glucocorticoid, prednisolone. Both steroids increased CE formation from two folds, in the presence of cholesterol-liposomes, to five folds, in the presence of modified low-density lipoprotein. Progestero ne (0.1-1 mu mol/L), added during glucocorticoid treatment, blocked this in crease. The progesterone block: 1) was duplicated by the steroid receptor i nhibitor RU40555; 2) was not reversed by hormone removal; and 3) reflected inhibition of glucocorticoid-induced increases in messenger RNA for acyl-Co A-cholesterol:acyl transferase. Thus, progesterone exerted two effects on m acrophages: it acutely inhibited CE formation, and it prevented glucocortic oid-induced increases in acyl-CoA-cholesterol-acyl transferase gene express ion and CE synthesis.