Immunology

Estrogen Receptor's Two Faces

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Science  24 Jun 2011:
Vol. 332, Issue 6037, pp. 1485
DOI: 10.1126/science.332.6037.1485-c

Many autoimmune diseases, including multiple sclerosis (MS), are more prevalent in women. This, coupled with prior findings implicating a role for the estrogen receptor (ER) in MS, prompted Saijo et al. to uncover the underlying molecular mechanisms. After determining that microglia, resident myeloid cells in the brain, primarily express ERβ, the authors showed that depending on the ligand, signaling through ERβ could either induce or inhibit proinflammatory gene expression. 17β-estradiol, which is more prevalent in women, drove expression of proinflammatory genes, whereas 5-androsten-3β,17β-diol (ADIOL) inhibited them. This occurred because ADIOL, but not 17β-estradiol, led to the recruitment of CtBP corepressor complexes, which functioned with ERβ and the transcription factor AP-1 to shut down proinflammatory gene expression. In women, this pathway may be antagonized because of increased amounts of 17β-estradiol, which competes with ADIOL for binding to ERβ and does not induce the recruitment of CtBP. Synthetic ligands that signaled similarly to ADIOL were protective and therapeutic in a mouse model of MS, which suggests that this pathway may be a useful target for therapeutic intervention.

Cell 13, 584 (2011).

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