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

Elife. 2014 Apr 25;3:e02057. doi: 10.7554/eLife.02057.

Abstract

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. In this study, we report that resveratrol acts as a pathway-selective estrogen receptor-α (ERα) ligand to modulate the inflammatory response but not cell proliferation. A crystal structure of the ERα 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 TNFα genes modulated by resveratrol and estradiol. Furthermore, the ability of resveratrol to suppress interleukin-6 transcription was shown to require ERα and several ERα coregulators, suggesting that ERα functions as a primary conduit for resveratrol activity.DOI: http://dx.doi.org/10.7554/eLife.02057.001.

Keywords: estrogen receptor; inflammation; resveratrol; transcription regulation; x-ray crystallography.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylate Kinase / metabolism
  • Cyclic AMP / metabolism
  • Estrogen Receptor alpha / chemistry
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Humans
  • Inflammation / metabolism*
  • Interleukin-6 / genetics
  • Ligands
  • MCF-7 Cells
  • Promoter Regions, Genetic
  • Protein Conformation
  • Resveratrol
  • Signal Transduction / drug effects*
  • Stilbenes / pharmacology*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Estrogen Receptor alpha
  • Interleukin-6
  • Ligands
  • Stilbenes
  • Tumor Necrosis Factor-alpha
  • Cyclic AMP
  • Adenylate Kinase
  • Resveratrol