TLR4 Signaling Inhibitory Pathway Induced by Green Tea Polyphenol Epigallocatechin-3-Gallate through 67-kDa Laminin Receptor
TLR4 Signaling Inhibitory Pathway Induced by Green Tea Polyphenol Epigallocatechin-3-Gallate through 67-kDa Laminin Receptor
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DOI：
10.4049/jimmunol.0903742
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发表时间：
2010-07-01
影响因子：
4.4
通讯作者：
Tachibana, Hirofumi
中科院分区：
文献类型：
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作者：
Byun, Eui Hong;Fujimura, Yoshinori;Tachibana, Hirofumi
表没食子儿茶素-3-没食子酸酯（EGCG）是绿色茶的主要活性多酚，已被证明可下调巨噬细胞中的炎症反应;然而，其潜在机制尚不清楚。最近，我们确定了67-kDa层粘连蛋白受体（67 LR）作为细胞表面的EGCG受体介导的抗癌作用的EGCG在生理相关浓度（0.1-1 μ M）。在这项研究中，我们显示的TLR 4信号转导的下调，在1 μ M的EGCG在巨噬细胞的分子基础。抗67 LR抗体处理或RNA干扰介导的67 LR沉默导致EGCG对LPS诱导的下游信号通路和靶基因表达的激活的抑制作用的废除。此外，我们发现EGCG通过67 LR降低TLR 4的表达。有趣的是，EGCG诱导了Toll相互作用蛋白（Tollip）的快速上调，Toll相互作用蛋白是TLR信号传导的负调节因子，而这种EGCG作用可通过67 LR沉默或抗67 LR Ab治疗来阻止。RNA干扰介导的Tollip沉默损害了EGCG的TLR 4信号抑制活性。总之，这些发现表明，67 LR在介导生理相关的EGCG的抗炎作用中起着关键作用，并且Tollip表达可以通过67 LR进行调节。这些结果为了解TLR 4信号通路的负调控机制和随后的炎症反应提供了新的见解，这些炎症反应与许多慢性疾病的发展和进展有关。免疫学杂志，2010，185：33-45。
Epigallocatechin-3-gallate (EGCG), a major active polyphenol of green tea, has been shown to downregulate inflammatory responses in macrophages; however, the underlying mechanism has not been understood. Recently, we identified the 67-kDa laminin receptor (67LR) as a cell-surface EGCG receptor that mediates the anticancer action of EGCG at physiologically relevant concentrations (0.1-1 mu M). In this study, we show the molecular basis for the downregulation of TLR4 signal transduction by EGCG at 1 mu M in macrophages. Anti-67LR Ab treatment or RNA interference-mediated silencing of 67LR resulted in abrogation of the inhibitory action of EGCG on LPS-induced activation of downstream signaling pathways and target gene expressions. Additionally, we found that EGCG reduced the TLR4 expression through 67LR. Interestingly, EGCG induced a rapid upregulation of Toll-interacting protein (Tollip), a negative regulator of TLR signaling, and this EGCG action was prevented by 67LR silencing or anti-67LR Ab treatment. RNA interference-mediated silencing of Tollip impaired the TLR4 signaling inhibitory activity of EGCG. Taken together, these findings demonstrate that 67LR plays a critical role in mediating anti-inflammatory action of a physiologically relevant EGCG, and Tollip expression could be modulated through 67LR. These results provide a new insight into the understanding of negative regulatory mechanisms for the TLR4 signaling pathway and consequent inflammatory responses that are implicated in the development and progression of many chronic diseases. The Journal of Immunology, 2010, 185: 33-45.