Estrogen receptor inhibits interleukin-6 gene expression by disruption of nuclear factor κB transactivation

The estrogen receptor (ER) suppresses interleukin-6 (IL-6) gene expression through interaction with nuclear factor κB (NF-κB) in a hormone-dependent manner. Classic ER binding to DNA is not required and the mechanism of repression is unclear. Previously reported studies suggest that the interference of NF-κB binding to DNA by ER may play an important role. An alternative model for repression would be the disruption of NF-κB transactivation. In the present study, gel shift assays were used to examine the binding of RelA and p50 dimers to the IL-6 promoter in the presence of ER. The effect of ER on NF-κB transactivation was studied independent of NF-κB binding to DNA using the mammalian one-hybrid system. ER had little effect on the binding of homodimers or heterodimers of RelA and p50 to the IL-6 promoter. In transfection experiments, both ERα and ERβ inhibited NF-κB-mediated expression in a hormone dependent manner with repression also dependent upon dimerization of RelA with p50. Mutant ER that is unable to transactivate failed to repress NF-κB expression, but deletion of the N-terminal portion of the receptor had no effect. Taken together, these results suggest that the disruption of NF-κB-mediated transactivation plays a significant role in ER inhibition of IL-6 gene expression.