When it was discovered, resveratrol was thought to be the key to longevity. The component in grapes and red wine, blueberries, cranberries, mulberries, peanuts and pistachios is known to be associated with reducing “bad cholesterol,” heart disease and some types of cancer. Researchers touted its potential benefits including anti-aging, inflammation and metabolism. Despite the potential, the drawback was bioavailability and efficiency. Now, researchers may have uncovered the molecular pathway resveratrol uses to reduce inflammation, which could lead to new drug discoveries.
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have now identified one of the molecular pathways that resveratrol uses to achieve its beneficial action. They found that resveratrol controls the body’s inflammatory response as a binding partner with the estrogen receptor without stimulating estrogenic cell proliferation, which is good news for its possible use as a model for drug design.
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. A recent study shows 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.
“Estrogen has beneficial effects on conditions like diabetes and obesity but may increase cancer risk,” said Kendall Nettles, a TSRI associate professor who led the study. “What hasn’t been well understood until now is that you can achieve those same beneficial effects with something like resveratrol.”
The problem with resveratrol, Nettles said, is that it really doesn’t work very efficiently in the body. “Now that we understand that we can do this through the estrogen receptor, there might compounds other than resveratrol out there that can do the same thing—only better,” he said.
“Our findings should lead scientists to reconsider the estrogen receptor as a main target of resveratrol—and any analogues,” said Jerome C. Nwachukwu, the first author of the study and a research associates in the Nettles laboratory. “It has gotten swept under the rug.”
In the new study, Nettles, Nwachukwu and their colleagues found that resveratrol is an effective inhibitor of interleukin 6 (IL-6), a pro-inflammatory protein that is part of the immune system (although IL-6 can be anti-inflammatory during exercise). High levels of IL-6 are also associated with poor breast cancer patient survival. According to the study, resveratrol regulates IL-6 without stimulating cell proliferation by altering a number of co-regulators of the estrogen receptor.
In addition to Nwachukwu and Nettles, other authors of the study, “Resveratrol Modulates the Inflammatory Response via An Estrogen Receptor-Signal Integration Network,” include Sathish Srinivasan, Nelson E. Bruno , Travis S. Hughes, Julie A. Pollock, Olsi Gjyshi, Valerie Cavett, Jason Nowak, Ruben D. Garcia-Ordonez , Patrick R. Griffin, Douglas J. Kojetin and Michael D. Conkright of TSRI; Alex A. Parent and John A. Katzenellenbogen of the University of Illinois; and René Houtman of PamGene International, The Netherlands.
The study was published as an accepted manuscript in the online journal eLife, a publication supported by the Howard Hughes Medical Institute, the Max Planck Society and the Wellcome Trust.