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* Western Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture and Department of Nutrition, University of California, Davis, CA 95616;
Division of Infectious Disease and Immunology, University of Massachusetts Medical School, Worcester, MA 01605;
Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702; and
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
TLRs can activate two distinct branches of downstream signaling pathways. MyD88 and Toll/IL-1R domain-containing adaptor inducing IFN-
(TRIF) pathways lead to the expression of proinflammatory cytokines and type I IFN genes, respectively. Numerous reports have demonstrated that resveratrol, a phytoalexin with anti-inflammatory effects, inhibits NF-
B activation and other downstream signaling pathways leading to the suppression of target gene expression. However, the direct targets of resveratrol have not been identified. In this study, we attempted to identify the molecular target for resveratrol in TLR-mediated signaling pathways. Resveratrol suppressed NF-B activation and cyclooxygenase-2 expression in RAW264.7 cells following TLR3 and TLR4 stimulation, but not TLR2 or TLR9. Further, resveratrol inhibited NF-B activation induced by TRIF, but not by MyD88. The activation of IFN regulatory factor 3 and the expression of IFN- induced by LPS, poly(I:C), or TRIF were also suppressed by resveratrol. The suppressive effect of resveratrol on LPS-induced NF-B activation was abolished in TRIF-deficient mouse embryonic fibroblasts, whereas LPS-induced degradation of IB
and expression of cyclooxygenase-2 and inducible NO synthase were still inhibited in MyD88-deficient macrophages. Furthermore, resveratrol inhibited the kinase activity of TANK-binding kinase 1 and the NF-B activation induced by RIP1 in RAW264.7 cells. Together, these results demonstrate that resveratrol specifically inhibits TRIF signaling in the TLR3 and TLR4 pathway by targeting TANK-binding kinase 1 and RIP1 in TRIF complex. The results raise the possibility that certain dietary phytochemicals can modulate TLR-derived signaling and inflammatory target gene expression and can alter susceptibility to microbial infection and chronic inflammatory diseases.
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