Estrogen inhibits NFκB-dependent inflammation in brain endothelium without interfering with IκB degradation

The protective effects of 17beta-estradiol in cerebral ischemia may be partially due to the blockade of leukocyte adhesion in cerebral endothelial cells, although the molecular mechanisms are not well understood. We report that 17beta-estradiol (E-2), but not the alpha-enantiomer, inhibited the basal and interleukin-1beta (IL-1beta)-mediated expression of the intercellular adhesion molecule type I (ICAMI) and NFkappaB activation, in cultured brain endothelial cells. However, the degradation of IKB-alpha, which is an essential requirement for the translocation of NFkappaB to the nucleus, and a common biological target to suppress NFkappaB activation, was not halted by E-2. These findings indicate that decreased expression of adhesion molecules may account for the capacity E-2 to reduce adhesion of leukocytes in cerebral endothelium in vivo, and suggest the existence of brain-specific, estrogen-sensitive pathways, other than IkappaB-alpha-regulation, to modulate NFkappaB. The stereoselectivity of the E-2 effect is consistent with an estrogen receptor-mediated mechanism.