Specific inhibition of MyD88-independent signaling pathways of TLR3 and TLR4 by resveratrol: Molecular targets are TBK1 and RIP1 in TRIF complex

Hyung S. Youn, Joo Y. Lee, Katherine A. Fitzgerald, Howard A. Young, Shizuo Akira, Daniel H. Hwang

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195 Citations (Scopus)

Abstract

TLRs can activate two distinct branches of downstream signaling pathways. MyD88 and Toll/IL-1R domain-containing adaptor inducing IFN-β (TRIF) pathways lead to the expression of proinflammatory cytokines and type IIFN genes, respectively. Numerous reports have demonstrated that resveratrol, a phytoalexin with anti-inflammatory effects, inhibits NF-κB 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 NFκB activation and cyclooxygenase-2 expression in RAW264.7 cells following TLR3 and TLR4 stimulation, but not TLR2 or TLR9. Further, resveratrol inhibited NF-κB activation induced by TRIF, but not by MyD88. The activation of IFN regulatory factor 3 and the expression of IFN-β induced by LPS, poly(I:C), or TRIF were also suppressed by resveratrol. The suppressive effect of resveratrol on LPS-induced NF-κB activation was abolished in TRIF-deficient mouse embryonic fibroblasts, whereas LPS-induced degradation of κBα 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-κB 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.

Original languageEnglish (US)
Pages (from-to)3339-3346
Number of pages8
JournalJournal of Immunology
Volume175
Issue number5
StatePublished - Sep 1 2005

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Phosphotransferases
Cyclooxygenase 2
Interferon Regulatory Factor-3
Gene Expression
resveratrol
Phytochemicals
Nitric Oxide Synthase
Chronic Disease
Anti-Inflammatory Agents
Fibroblasts
Macrophages
Cytokines
Infection
Genes
polyriboinosinic-polyribocytidylic acid
phytoalexins

ASJC Scopus subject areas

  • Immunology

Cite this

Youn, H. S., Lee, J. Y., Fitzgerald, K. A., Young, H. A., Akira, S., & Hwang, D. H. (2005). Specific inhibition of MyD88-independent signaling pathways of TLR3 and TLR4 by resveratrol: Molecular targets are TBK1 and RIP1 in TRIF complex. Journal of Immunology, 175(5), 3339-3346.

Specific inhibition of MyD88-independent signaling pathways of TLR3 and TLR4 by resveratrol : Molecular targets are TBK1 and RIP1 in TRIF complex. / Youn, Hyung S.; Lee, Joo Y.; Fitzgerald, Katherine A.; Young, Howard A.; Akira, Shizuo; Hwang, Daniel H.

In: Journal of Immunology, Vol. 175, No. 5, 01.09.2005, p. 3339-3346.

Research output: Contribution to journalArticle

Youn, HS, Lee, JY, Fitzgerald, KA, Young, HA, Akira, S & Hwang, DH 2005, 'Specific inhibition of MyD88-independent signaling pathways of TLR3 and TLR4 by resveratrol: Molecular targets are TBK1 and RIP1 in TRIF complex', Journal of Immunology, vol. 175, no. 5, pp. 3339-3346.
Youn, Hyung S. ; Lee, Joo Y. ; Fitzgerald, Katherine A. ; Young, Howard A. ; Akira, Shizuo ; Hwang, Daniel H. / Specific inhibition of MyD88-independent signaling pathways of TLR3 and TLR4 by resveratrol : Molecular targets are TBK1 and RIP1 in TRIF complex. In: Journal of Immunology. 2005 ; Vol. 175, No. 5. pp. 3339-3346.
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