Resveratrol Induces the Heat-Shock Response and Protects Human Cells from Severe Heat Stress

Molecular chaperones play key roles in protein quality control, signal transduction, proliferation, and cell death, and confer cytoprotection and assure survival after environmental stress. The heat-shock response is implicated in a variety of conditions including ischemic diseases, infection and immunity, neurodegeneration, and aging. Physiologic and pharmacologic chaperone inducers were shown to be an efficient therapeutic approach in different acute and chronic diseases. Here we characterize resveratrol, a polyphenol from red wine, as an inducer of the heat-shock response. Resveratrol activated the heat-shock promoter and the expression of the major chaperone Hsp70 in cell lines and in human peripheral lymphocytes, comparable to moderate heat stress. This effect was not due to its antioxidant property, because 5 mM N-acetylcysteine was unable to activate the heat-shock response. Moreover, resveratrol failed to upregulate Grp78, and tunicamycin was unable to induce Hsp70, suggesting that the resveratrol-induced heat-shock response was not mediated by canonic endoplasmic reticulum stress. Resveratrol synergized with mild to moderate heat shock and conferred cytoprotection against severe heat stress. Our results reveal resveratrol as a chaperone inducer that may contribute to its pleiotropic effects in ameliorating stress and promoting longevity.