Estrogens and glucocorticoids inhibit endothelial vascular cell adhesion molecule-1 expression by different transcriptional mechanisms

The antiatherogenic effect of estrogen is mediated, in part, by inhibitory effects on endothelial vascular cell adhesion molecule-1 (VCAM-1) expression. To determine the mechanism by which estrogen regulates VCAM-1 expression, we compared the effect of 17 beta-estradiol (E-2) and of the glucocorticoid dexamethasone (Dex) on lipopolysaccharide (LPS)-induced VCAM-1 expression in human endothelial cells. E-2 decreased LPS-induced VCAM-1 mRNA and protein expression to a greater extent than Dex. Dex, but not E-2, stabilized VCAM-1 mRNA. This correlated with inhibition of monocytoid 11937 eel adhesion to endothelial cells. Transfection of endothelial cells with a functional VCAM-1 promoter construct showed that E-2 inhibited LPS-induced VCAM-I gene transcription more potently than did Dex. However, using a truncated construct containing only the nuclear factor-kappa B (NF-kappa B)-responsive elements but lacking the consensus sequences for activator protein-1 (AP-1) and GATA, E-2 and Dex had similar inhibitory effects. Consistently, gel-shift assays showed that E-2 and Dex comparably inhibit LPS-induced activation of NF-kappa B, whenas E-2 inhibited LPS-induced activation of AP-I and GATA to a greater extent than Dex. E-2 inhibition of NF-kappa B after LPS treatment was associated with decreased inhibitor kappa B (I kappa B) kinase activity and with a stabilization of the NF-kappa B inhibitor I kappa B alpha. These results indicate that E-2 decreases VCAM-I gene expression through the inhibition of NF-kappa B, AP-1, and GATA and suggest novel mechanisms for the antiatherogenic effect of estrogen on the vascular wall.