Green tea catechin, epigallocatechin gallate, suppresses signaling by the dsRNA innate immune receptor RIG-I.
Green tea catechin, epigallocatechin gallate, suppresses signaling by the dsRNA innate immune receptor RIG-I.
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DOI：
10.1371/journal.pone.0012878
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发表时间：
2010-09-22
期刊：
影响因子：
3.7
通讯作者：
Cheng Kao C
中科院分区：
文献类型：
--
作者：
Ranjith-Kumar CT;Lai Y;Sarisky RT;Cheng Kao C
先天免疫系统是抵御病原体感染的第一道防线。维甲酸诱导基因I(RIG-I)受体识别三磷酸化的单链RNA和双链RNA，启动干扰素反应的下游信号。然而，这些受体的不受调控的活性可能会导致自身免疫性疾病。我们试图识别能够专门调节RIG-I信号的小分子。表没食子儿茶素没食子酸酯(EGCG)是一种存在于绿茶中的多酚儿茶素，在小分子筛查中被鉴定出来。在HEK293T细胞中发现它与RIG-I结合，并在低微摩尔浓度下抑制其信号转导。此外，EGCG剂量依赖性地抑制重组RIG-I的ATPase活性，但不竞争RIG-I与RNA或与ATP的相互作用。EGCG不抑制Toll样受体3、4、9的信号转导，也不抑制连接蛋白IPS-1的结构性信号转导。构效关系分析表明，EGCG及其同分异构体GCG和含二没食子酸酯的化合物茶黄素3，3‘-二没食子酸酯(TFDG)是RIG-I的有效抑制剂。EGCG还能抑制内源性RIG-I信号通路完整的BEAS-2B细胞分泌IL-6和合成干扰素-β。EGCG及其衍生物可能作为RIG-I介导的免疫反应的调节剂具有潜在的治疗用途。
The Innate immune system constitutes the first line of defense against pathogen infections. The Retinoic acid-inducible gene I (RIG-I) receptor recognizes triphosphorylated ssRNAs and dsRNA to initiate downstream signaling of interferon response. However, unregulated activity of these receptors could lead to autoimmune diseases. We seek to identify small molecules that can specifically regulate RIG-I signaling. Epigallocatechin gallate (EGCG), a polyphenolic catechin present in green tea, was identified in a small molecule screen. It was found to bind RIG-I and inhibits its signaling at low micromolar concentrations in HEK293T cells. Furthermore, EGCG dose-dependently inhibited the ATPase activity of recombinant RIG-I but did not compete with RIG-I interaction with RNA or with ATP. EGCG did not inhibit signaling by Toll-like receptors 3, 4, 9 or constitutive signaling by the adapter protein IPS-1. Structure activity relationship analysis showed that EGCG, its epimer GCG and a digallate-containing compound, theaflavin 3,3′ digallate (TFDG) were potent RIG-I inhibitors. EGCG also inhibited IL6 secretion and IFN- β mRNA synthesis in BEAS-2B cells, which harbors intact endogenous RIG-I signaling pathway. EGCG and its derivatives could have potential therapeutic use as a modulator of RIG-I mediated immune responses.
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