The role of CBP in estrogen receptor cross-talk with nuclear factor-κB in HepG2 cells

Functional interactions or cross-talk between ligand-activated nuclear receptors and the proinflammatory transcription factor nuclear factor-kappa B (NF-kappa B) may play a major role in ligand-mediated modification of diseases processes. In particular, the cardioprotective effects of estrogen replacement therapy are thought to be due in part to the ability of ligand-bound estrogen receptor (ER) to inhibit NF-kappa B function. In the current study 17 beta-estradiol-bound ER alpha interfered with cytokine-induced activation of a NF-kappa B reporter in HepG2 cells. The estrogen metabolite, 17 alpha-ethinyl estradiol, and the phytoestrogen, genistein, were also effective inhibitors of NF-kappa B activation, whereas tamoxifen, 4-hydroxytamoxifen, and raloxifene were inactive. This inhibition was reciprocal, as NF-kappa B interfered with the trans-activation properties of ER alpha. Ligand-bound ER alpha did not inhibit NF-kappa B binding to DNA, but it did decrease the histone acetyltransferase activity required for NF-kappa B transcriptional activity. Coexpression of the transcription coactivator CREB binding protein (CBP), but not steroid receptor coactivator 1a, reversed the ER alpha-mediated inhibition of NF-kappa B activity. Mammalian two-hybrid experiments also revealed that ligand-bound ER alpha can interact functionally with CBP-NF-kappa B complexes. We suggest that CBP targeting by ER alpha results in the inhibition of NF-kappa B and may occur through formation of transcriptionally inert multimeric complexes that are dependent upon the nature of the ER alpha ligand.