Immunomodulatory activity of resveratrol: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production

trans-Resveratrol, a phytoalexin found in grapes, wine, and other plant pro ducts, has been shown to have anti-inflammatory, antioxidant, and antitumor activities. Many of these beneficial effects of resveratrol require partic ipation of the cells of the immune system; however, the effect of resveratr ol on the development of immunological responses remains unknown. We have i nvestigated the effect of resveratrol on mitogen/antigen-induced proliferat ion of splenic lymphocytes, induction of cytotoxic T lymphocytes (CTLs) and lymphokine activated killer (LAK) cells, and the production of the cytokin es interferon (IFN)-gamma, interleukin (IL)-2, tumor necrosis factor (TNF)- alpha, and IL-12. We found that mitogen-, IL-2-, or alloantigen-induced pro liferation of splenic lymphocytes and the development of antigen-specific C TLs were suppressed significantly at 25-50 muM resveratrol. The generation of LAK cells at similar concentrations was less sensitive to the suppressiv e effect of resveratrol. The suppression of cell proliferation and CTL gene ration by resveratrol was not only reversible, but in some cases the respon se (mitogen/IL-2-induced proliferation and CTL generation) was actually enh anced following pretreatment of cells with resveratrol. Resveratrol also in hibited the production of IFN-gamma and IL-2 by splenic lymphocytes, and th e production of TNF-alpha and IL-12 by peritoneal macrophages. The inhibiti on of cytokine production by resveratrol was irreversible. Further, resvera trol blocked the activation of the transcription factor NF-kappaB without a ffecting basal NF-KB activity. The latter result suggests that resveratrol inhibits cell proliferation, cell-mediated cytotoxicity, and cytokine produ ction, at least in part through the inhibition of NF-kappaB activation. (C) 2001 Elsevier Science Inc. All rights reserved.