Submitted to: Biochemical Pharmacology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 6/15/2006
Publication Date: 6/21/2006
Citation: Youn, H.S., Lee, J.Y., Saotoh, S.I., Miyake, K., Kang, K.W., Choi, Y., Hwang, D.H. 2006. Suppression of myd88- and trif-dependent signaling pathways of toll-like receptor by (-)-epigallocatechin-3-gallate, a polyphenol component of green tea. Biochemical Pharmacology; Elsevier 72 (2006) 850-859. Interpretive Summary: A polyphenol, epigallocatechin gallate inhibits the signaling pathways of Toll-like receptor 4 and target dgene expression. The molecular target is TBK1 kinase. These results suggest that the anti-inflammatory effects of epigallocatechin is mediated at least in part through the inhibition of TLR4 sinaling pathways and target gene expression.
Technical Abstract: Toll-like receptors (TLRs) play an important role in recognition of microbial components and induction of innate immunity. The microbial components trigger the activation of two downstream signaling pathways of TLR4; MyD88- and TRIF-dependent pathways. -)-epigallocatechin-3-gallate (EGCG), a flavonoid found in green tea, is known to inhibit NF-'B activation induced by many pro-inflammatory stimuli. The direct molecular target of EGCG was shown to inhibit the activity of IKK' which is the key kinase in the canonical pathway for NF-'B activation in MyD88-dependent pathway of TLRs. However, it is not known whether EGCG inhibits TRIF-dependent pathway through which more than 70 % of LPS-induced genes are regulated. Therefore, we attempted to identify the molecular target of EGCG in TRIF-dependent pathways of TLR3 and TLR4. EGCG inhibited the activation of IFN regulatory factor 3 induced by LPS or poly[I:C]. Furthermore, EGCG suppressed the activation of IRF3 induced by the overexpression of TRIF, and inhibited the kinase activity of TBK1. However, EGCG did not inhibit activation of IRF3 induced by overexpression of constitutively active IRF3. These results suggest that the molecular target of EGCG is TBK1 in TRIF-dependent signaling pathways of TLR3 and TLR4. Therefore, our results suggest that green tea flavonoids can modulate both MyD88- and TRIF-dependent signaling pathways of TLRs and subsequent inflammatory target gene expression.