Abstract
Resveratrol (trans-3,5,4′-trihydroxystilbene), a polyphenolic compound found in plant products, including red grapes, exhibits anticancer, antioxidant, and anti-inflammatory properties. Using an animal model of multiple sclerosis (MS), we investigated the use of resveratrol for the treatment of autoimmune diseases. We observed that resveratrol treatment decreased the clinical symptoms and inflammatory responses in experimental allergic encephalomyelitis (EAE)-induced mice. Furthermore, we observed significant apoptosis in inflammatory cells in spinal cord of EAE-induced mice treated with resveratrol compared with the control mice. Resveratrol administration also led to significant down-regulation of certain cytokines and chemokines in EAE-induced mice including tumor necrosis factor-α, interferon-γ, interleukin (IL)-2, IL-9, IL-12, IL-17, macrophage inflammatory protein-1α (MIP-1α), monocyte chemoattractant protein-1 (MCP-1), regulated on activation normal T-cell expressed and secreted (RANTES), and Eotaxin. In vitro studies on the mechanism of action revealed that resveratrol triggered high levels of apoptosis in activated T cells and to a lesser extent in unactivated T cells. Moreover, resveratrol-induced apoptosis was mediated through activation of aryl hydrocarbon receptor (AhR) and estrogen receptor (ER) and correlated with up-regulation of AhR, Fas, and FasL expression. In addition, resveratrol-induced apoptosis in primary T cells correlated with cleavage of caspase-8, caspase-9, caspase-3, poly(ADP-ribose) polymerase, and release of cytochrome c. Data from the present study demonstrate, for the first time, the ability of resveratrol to trigger apoptosis in activated T cells and its potential use in the treatment of inflammatory and autoimmune diseases including, MS.
Footnotes
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This work was funded in part by National Institutes of Health grants P01-AT003961, R01-ES09098, R01-DA016545, R01-AI053703, R01-HL058641, R21-DA014885, and F31-ES11562, by A. D. Williams Trust Funds (to N.P.S.), and by an American Cancer Society Institutional Grant (to N.P.S.).
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.107.038984.
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ABBREVIATIONS: resveratrol, trans-3,5,4′-trihydroxystilbene; AP-1, activator protein-1; AhR, aryl hydrocarbon receptor; ER, estrogen receptor; ConA, concanavalin A; mAb, monoclonal antibody; TNF-α, tumor necrosis factor-α; INF-γ, interferon-γ; IL, interleukin; RANTES, regulated on activation normal T-cell expressed and secreted; MIP, macrophage inflammatory protein; MCP, monocyte chemoattractant protein; Z-, N-benzyloxycarbonyl-; FMK, fluoromethyl ketone; PARP, poly(ADP-ribose) polymerase; HRP, horseradish peroxidase; Ab, antibody; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; ANF, α-naphthoflavone; DMSO, dimethyl sulfoxide; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; MOG, myelin oligodendrocyte glycoprotein; PCR, polymerase chain reaction; ELISA, enzyme-linked immunosorbent assay; BSA, bovine serum albumin; DC, dendritic cell; bp, base pair(s); TAM, tamoxifen; DiOC6, 3,3′-dihexyloxacarbocyanine iodide; PI, propidium iodide; KO, knockout; ΔΨm, mitochondrial membrane potential.
- Received June 12, 2007.
- Accepted September 13, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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