Suppression of MyD88- and TRIF-dependent signaling pathways of Toll-like receptor by (-)-epigallocatechin-3-gallate, a polyphenol component of green tea.
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 TLRs; MyD88- and/or TRIF-dependent pathways leading to activation of NF-kappaB. (-)-Epigallocatechin-3-gallate (EGCG), a flavonoid found in green tea, is known to inhibit NF-kappaB activation induced by many pro-inflammatory stimuli. EGCG was shown to inhibit the activity of IKKbeta which is the key kinase in the canonical pathway for NF-kappaB activation in MyD88-dependent pathway of TLRs. However, it is not known whether EGCG inhibits TRIF-dependent pathway through which more than 70% of lipopolysaccharide (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 (IRF3) induced by LPS, poly[I:C], or the overexpression of TRIF. The inhibition of IRF3 activation by EGCG was mediated through the suppression of 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.
Youn
Hyung S
HS
USDA, ARS, Western Human Nutrition Research Center, and Department of Nutrition, University of California, Davis, Meyer Hall, One Shields Ave., CA 95616, USA. hyoun@suv.ac.kr
Lee
Joo Y
JY
Saitoh
Shin I
SI
Miyake
Kensuke
K
Kang
Keon W
KW
Choi
Yong J
YJ
Hwang
Daniel H
DH
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D000818:Animals; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology; D059808:Polyphenols; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013662:Tea / Q000737:chemistry; D051195:Toll-Like Receptor 2 / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology; D051193:Toll-Like Receptors / Q000502:physiology*; D014162:Transfection; D000097782:NF-kappaB-Inducing Kinase
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D002392:Catechin; D051546:Cyclooxygenase 2; D005419:Flavonoids; D051550:I-kappa B Kinase; D007371:Interferon-gamma; D008156:Luciferases; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D010636:Phenols; D059808:Polyphenols; D017346:Protein Serine-Threonine Kinases; D013662:Tea; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D000097782:NF-kappaB-Inducing Kinase; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; C470409:TICAM1 protein, human; C045651:epigallocatechin gallate; C403191:TBK1 protein, human