Resveratrol and its metabolites inhibit pro-inflammatory effects of lipopolysaccharides in U-937 macrophages in plasma-representative concentrations

• Published in: Food & function 2014-01, Vol.5 (1), p.74-84
• Main Authors: Walker, Jessica, Schueller, Katharina, Schaefer, Lisa-Marie, Pignitter, Marc, Esefelder, Laura, Somoza, Veronika
• Format: Article
• Language: English
• Subjects: Anti-Inflammatory Agents - metabolism; Anti-Inflammatory Agents - pharmacology; Down-Regulation - drug effects; Escherichia; Humans; Inflammation - drug therapy; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Interleukin-1 - genetics; Interleukin-1 - immunology; Interleukin-6 - genetics; Interleukin-6 - immunology; Lipopolysaccharides - immunology; Macrophages - drug effects; Macrophages - immunology; Stilbenes - metabolism; Stilbenes - pharmacology; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology; U937 Cells
• ISSN: 2042-6496; 2042-650X
• DOI: 10.1039/c3fo60236b

Resveratrol has been shown to exploit various biological activities, including an anti-inflammatory activity. However, resveratrol is metabolized by phase II enzymes post-absorption to predominantly form glucuronides and sulfates. To investigate the anti-inflammatory effects of resveratrol and its dominating sulfated and glucuronated metabolites formed in vivo , U-937 macrophages were chosen as an immune-competent model system, known to release cytokines upon lipopolysaccharide stimulation. U-937 cells were stimulated with lipopolysaccharides from Escherichia coli ( E. coli -LPS) to evoke an inflammatory reaction, and pre- or co-incubated with 1 or 10 μM of resveratrol (RES), resveratrol-3-sulfate (R3S), resveratrol-disulfates (RDS), resveratrol-3-glucuronide or resveratrol-4′-glucuronide. Time dependent gene expression of IL-6, IL-1α/β and IL-1R by qPCR was studied at 1 h, 3 h, 6 h, 9 h, and 24 h of incubation, and the release of IL-6 and TNF-α, after 6 h was analysed by means of non-magnetic or magnetic bead analysis. As a result, 10 μM resveratrol completely inhibited the E. coli -LPS-induced release of IL-6, while resveratrol-3-sulfate and resveratrol-disulfates decreased it by respective 84.2 ± 29.4% and 52.3 ± 39.5%. Whereas TNF-α release was reduced by 48.1 ± 15.4%, 33.0 ± 10.0% and 46.7 ± 8.7% by RES, R3S and RDS, respectively. These results show that not only resveratrol but also resveratrol-3-sulfate and resveratrol-disulfates exhibit an anti-inflammatory potential by counteracting an inflammatory challenge in U-937 macrophages at plasma representative concentrations. Resveratrol sulfates inhibit the lipopolysaccharides-induced release and gene expression of interleukin-6 and TNF-α in concentrations of 1 or 10 μM, found in plasma after intake of resveratrol.