Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network

Resveratrol has beneficial effects on aging, inflammation and metabolism, which are thought to result from activation of the lysine deacetylase, sirtuin 1 (SIRT1), the cAMP pathway, or AMP-activated protein kinase. Here we report that resveratrol acts as a pathway-selective estrogen receptor-alpha (ER alpha) ligand to modulate the inflammatory response but not cell proliferation. A crystal structure of the ER alpha ligand-binding domain (LBD) as a complex with resveratrol revealed a unique perturbation of the coactivator-binding surface, consistent with an altered coregulator recruitment profile. Gene expression analyses revealed significant overlap of TNF alpha genes modulated by resveratrol and estradiol. Furthermore, the ability of resveratrol to suppress interleukin-6 transcription was shown to require ER alpha and several ER alpha coregulators, suggesting that ER alpha functions as a primary conduit for resveratrol activity.