Suppression of MyD88- and TRIF-dependent signaling pathways of toll-like receptor by (-)-epigallocatechin-3-gallate, a polyphenol component of green tea
Suppression of MyD88- and TRIF-dependent signaling pathways of toll-like receptor by (-)-epigallocatechin-3-gallate, a polyphenol component of green tea
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DOI：
10.1016/j.bcp.2006.06.021
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发表时间：
2006-09-28
影响因子：
5.8
通讯作者：
Hwang, Daniel H.
中科院分区：
文献类型：
--
作者：
Youn, Hyung S.;Lee, Joo Y.;Hwang, Daniel H.
Toll样受体（TLR）在识别微生物组分和诱导先天免疫中起重要作用。微生物组分触发TLR的两个下游信号传导途径的激活; MyD 88-和/或TRIF-依赖性途径导致NF-κ B的激活。（-）-表没食子儿茶素-3-没食子酸酯（EGCG），一种在绿色茶中发现的类黄酮，已知抑制由许多促炎刺激诱导的NF-κ B活化。EGCG显示抑制IKK β的活性，IKK β是TLR的MyD 88依赖性途径中NF-κ B活化的经典途径中的关键激酶。然而，目前尚不清楚EGCG是否抑制TRIF依赖的途径，通过该途径调节超过70%的脂多糖（LPS）诱导的基因。因此，我们试图确定EGCG在TLR 3和TLR 4的TRIF依赖性途径中的分子靶点。EGCG可抑制LPS、poly[I：C]或TRIF过表达诱导的IFN调节因子3（IRF 3）的活化。EGCG对IRF 3激活的抑制是通过抑制TBK 1的激酶活性介导的。然而，EGCG并不抑制过表达诱导的IRF 3的激活。组成型活性IRF 3。这些结果表明，在TRIF依赖的TLR 3和TLR 4信号通路中，EGCG的分子靶点是TBK 1。因此，我们的研究结果表明，绿色茶黄酮类化合物可以调节MyD 88和TRIF依赖的TLR信号通路和随后的炎症靶基因表达。(c)2006年爱思唯尔公司All rights reserved.
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-kappa B. (-)-Epigallocatechin-3-gallate (EGCG), a flavonoid found in green tea, is known to inhibit NF-kappa B activation induced by many pro-inflammatory stimuli. EGCG was shown to inhibit the activity of IKK beta which is the key kinase in the canonical pathway for NF-kappa 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 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. (c) 2006 Elsevier Inc. All rights reserved.