Abstract —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 17β-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 U937 cell adhesion to endothelial cells. Transfection of endothelial cells with a functional VCAM-1 promoter construct showed that E ₂ inhibited LPS-induced VCAM-1 gene transcription more potently than did Dex. However, using a truncated construct containing only the nuclear factor-κB (NF-κB)–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-κB, whereas E ₂ inhibited LPS-induced activation of AP-1 and GATA to a greater extent than Dex. E ₂ inhibition of NF-κB after LPS treatment was associated with decreased inhibitor κB (IκB) kinase activity and with a stabilization of the NF-κB inhibitor IκBα. These results indicate that E ₂ decreases VCAM-1 gene expression through the inhibition of NF-κB, AP-1, and GATA and suggest novel mechanisms for the antiatherogenic effect of estrogen on the vascular wall. ( Circ Res. 2000;87:19-25.)