PHYSIOLOGICAL CONCENTRATIONS OF 17-BETA-ESTRADIOL INHIBIT THE SYNTHESIS OF NITRIC-OXIDE SYNTHASE IN MACROPHAGES VIA A RECEPTOR-MEDIATED SYSTEM

We investigated the effect of estrogen on inducible nitric oxide synth ase (iNOS), which is not well understood, in contrast to the known eff ect of estrogen on endothelial nitric oxide synthase (eNOS). When J774 cells, a murine macrophage cell line, were incubated with interferon- gamma and lipopolysaccharide, iNOS was induced, and a large amount of NO was released. Pre-or coincubation with 17 beta-estradiol inhibited this induction of iNOS protein and NO release; however, 17 beta-estrad iol did not have a direct effect on enzyme activity of iNOS. The analo g, 17 alpha-estradiol, did not have such an effect. Tamoxifen, an anti estrogen, and ICI182780, an estrogen-receptor antagonist, inhibited th e influence of 17 beta-estradiol on iNOS. Thus 17 beta-estradiol inhib ited the induction of iNOS by a classic receptor-mediated pathway. The inhibition of the NO release from iNOS by 17 beta-estradiol is in con trast to the reported augmentation of continuous NO release from eNOS. These harmonious effects of estrogen on iNOS and eNOS may have some r ole ill the antiatherosclerotic effects of 17 beta-estradiol.