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. 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.
Department of Cancer Biology, The Scripps Research Institute, Jupiter, United States.
Jerome C
JC
Nwachukwu
Department of Cancer Biology, The Scripps Research Institute, Jupiter, United States.
Sathish
S
Srinivasan
Department of Cancer Biology, The Scripps Research Institute, Jupiter, United States.
Nelson E
NE
Bruno
Department of Chemistry, University of Illinois, Urbana, United States.
Alexander A
AA
Parent
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, United States.
Travis S
TS
Hughes
Department of Chemistry, University of Illinois, Urbana, United States.
Julie A
JA
Pollock
Department of Cancer Biology, The Scripps Research Institute, Jupiter, United States.
Olsi
O
Gjyshi
Department of Cancer Biology, The Scripps Research Institute, Jupiter, United States.
Valerie
V
Cavett
Department of Cancer Biology, The Scripps Research Institute, Jupiter, United States.
Jason
J
Nowak
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, United States.
Ruben D
RD
Garcia-Ordonez
Nuclear Receptor Group, PamGene International, Den Bosch, Netherlands.
René
R
Houtman
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, United States.
Patrick R
PR
Griffin
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, United States.
Douglas J
DJ
Kojetin
Department of Chemistry, University of Illinois, Urbana, United States.
John A
JA
Katzenellenbogen
Department of Cancer Biology, The Scripps Research Institute, Jupiter, United States.
Michael D
MD
Conkright
Department of Cancer Biology, The Scripps Research Institute, Jupiter, United States knettles@scripps.edu.
Kendall W
KW
Nettles
D000263:Adenylate Kinase / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics; D008024:Ligands; D061986:MCF-7 Cells; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects*; D013267:Stilbenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D047628:Estrogen Receptor alpha; D015850:Interleukin-6; D008024:Ligands; D013267:Stilbenes; D014409:Tumor Necrosis Factor-alpha; D000242:Cyclic AMP; D000263:Adenylate Kinase; D000077185:Resveratrol
estrogen receptor; inflammation; resveratrol; transcription regulation; x-ray crystallography