Immunomodulatory activity of resveratrol: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production¹

Abstract

trans-Resveratrol, a phytoalexin found in grapes, wine, and other plant products, has been shown to have anti-inflammatory, antioxidant, and antitumor activities. Many of these beneficial effects of resveratrol require participation of the cells of the immune system; however, the effect of resveratrol on the development of immunological responses remains unknown. We have investigated the effect of resveratrol on mitogen/antigen-induced proliferation of splenic lymphocytes, induction of cytotoxic T lymphocytes (CTLs) and lymphokine activated killer (LAK) cells, and the production of the cytokines interferon (IFN)-γ, interleukin (IL)-2, tumor necrosis factor (TNF)-α, and IL-12. We found that mitogen-, IL-2-, or alloantigen-induced proliferation of splenic lymphocytes and the development of antigen-specific CTLs were suppressed significantly at 25–50 μM resveratrol. The generation of LAK cells at similar concentrations was less sensitive to the suppressive effect of resveratrol. The suppression of cell proliferation and CTL generation by resveratrol was not only reversible, but in some cases the response (mitogen/IL-2-induced proliferation and CTL generation) was actually enhanced following pretreatment of cells with resveratrol. Resveratrol also inhibited the production of IFN-γ and IL-2 by splenic lymphocytes, and the production of TNF-α and IL-12 by peritoneal macrophages. The inhibition of cytokine production by resveratrol was irreversible. Further, resveratrol blocked the activation of the transcription factor NF-κB without affecting basal NF-κB activity. The latter result suggests that resveratrol inhibits cell proliferation, cell-mediated cytotoxicity, and cytokine production, at least in part through the inhibition of NF-κB activation.

Introduction

Epidemiological and animal studies have demonstrated that plant-derived dietary constituents of food play an important role in the prevention of disease [1], [2]. A number of food components that inhibit the initiation and progression of cancer or otherwise influence the potential for disease outcome have been identified [3], [4], [5]. The beneficial effects of these dietary compounds have been attributed partly to the presence in food materials of numerous polyphenolic compounds with antioxidant and free radical scavenging properties [6], [7]. This conclusion is best supported by epidemiological studies showing a close association between low incidence of coronary heart disease and breast cancer [8], [9], [10] and moderate consumption of red wine containing natural polyphenolic compounds.

Resveratrol is a non-flavonoid polyphenolic compound found in grapes and the red wine prepared from them. Resveratrol has been shown to modulate lipoprotein metabolism [11], [12], eicosanoid synthesis [13], [14], [15], lipid oxidation [16], and platelet aggregation [13], [17]. Resveratrol also suppresses the induction of nitric oxide synthase and disrupts arachidonic acid metabolism by inhibiting cyclooxygenase-2 [18], [19]. Recently, resveratrol was shown to inhibit cellular processes associated with tumor initiation, promotion, and progression in vivo, and the development of pre-neoplastic lesions in mouse mammary glands in vitro[20]. In other studies, resveratrol inhibited the proliferation of breast, oral, liver, prostate, and colon cancer cell lines in a dose- and time-dependent manner [21], [22], [23], [24]. Resveratrol has also shown cardioprotective and neuroprotective activity in rats [25], [26].

We have reported previously that although resveratrol inhibits the growth of both normal hematopoietic progenitor cells and leukemia cell lines in a dose-related manner, the anti-proliferative effect of resveratrol on normal hematopoietic progenitor cells is less dramatic and reversible compared with that on leukemia cells [27]. Resveratrol induced apoptosis in leukemia cells, but not in normal hematopoietic cells. Additionally, hematopoietic progenitor cells treated with resveratrol fully maintained their capacity to reconstitute lethally irradiated mice hematologically. The antiproliferative and anti-inflammatory activity of resveratrol has been well documented in many studies, but its effect on the development of cellular immune responses and the production of cytokines has not been established. In the present study, we examined the effect of resveratrol on mitogen/antigen-induced proliferation of splenic lymphoid cells, the development of cell-mediated cytotoxicity, and the production of cytokines by lymphocytes and macrophages.