Reciprocal antagonism between estrogen receptor and NF-kappa B activity invivo

The functional interaction, or "cross-talk," between estrogen receptor (ER) and the proinflammatory transcription factor nuclear factor (NF)-kappaB de monstrated in vitro has been suggested to play a role in estrogen preventio n of cardiovascular disease. Here, we demonstrate that this reciprocal cros s-talk occurs in vivo. Ovariectomized C57BL/6 mice fed an atherogenic diet had increased hepatic levels of active NF-kappaB and numerous inflammatory genes, including MHC invariant chain (Ii), vascular cell adhesion molecule- 1, tumor necrosis factor-alpha, and RANTES. Treatment with 17 alpha -ethiny lestradiol (EE) strongly blocked induction of these genes but had no effect on their basal expression levels. ER was required for this activity, becau se the antagonist ICI 182,780 completely blocked the inhibitory activity of EE. Gene activation by EE was not required for inhibition of inflammatory gene expression, because both the phytoestrogen genistein and low doses of EE were effective in blocking inflammatory gene induction without inducing marker genes such as intestinal trefoil factor (ITF) or myo-inositol-1-phos phate synthase (IPS). The in vivo transcriptional interference was reciproc al, with EE induction of ITF and IPS greatly reduced in animals fed the ath erogenic diet versus chow-fed controls. This interference was specific to t he liver, because diet had no effect on uterine weight increases produced b y EE. Transfection experiments confirmed that the extent of inhibition of E R-mediated transcription by inflammatory stimuli correlated with the extent of NF-kappaB activation. These results suggest that the cross-talk between ER and NF-kappaB does occur in vivo and may indeed contribute significantl y to the cardioprotective effects of estrogen.