Distinct roles of unliganded and liganded estrogen receptors in transcriptional repression

The decline in estrogen levels during menopause is associated with increased cytokine production and inflammatory diseases. Estrogens exert anti-inflammatory effects by repressing cytokine genes, such as tumor necrosis factor-α (TNFα). The mechanisms involved in transcriptional repression by estrogens are virtually unknown. Here, we used chromatin immunoprecipitation to investigate how estrogens repress the autoinduction of the TNFα gene. TNFα assembled a transcriptional activation complex at the TNFα promoter that includes c-jun, p50-NFκB, p65-NFκB, CBP, Hsp90, and unliganded estrogen receptor (ER). Estradiol repressed TNFα gene expression by reversing the ligand-independent activation by ERα and the stimulatory actions of c-jun, NFκB, and CBP on transcription. Silencing of GRIP1 reversed the repression of TNFα and other cytokine genes by estradiol, demonstrating that GRIP1 is required for transcriptional repression and can act as a corepressor. Our study demonstrates that ERα is a TNFα-induced coactivator that becomes a repressor in the presence of estradiol by recruiting GRIP1.