Quercetin negatively regulates TLR4 signaling induced by lipopolysaccharide through Tollip expression
Quercetin negatively regulates TLR4 signaling induced by lipopolysaccharide through Tollip expression
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DOI：
10.1016/j.bbrc.2013.01.056
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发表时间：
2013-02-22
影响因子：
3.1
通讯作者：
Byun, Eui-Hong
中科院分区：
文献类型：
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作者：
Byun, Eui-Baek;Yang, Mi-So;Byun, Eui-Hong
多酚类化合物被认为是预防和治疗炎症相关慢性疾病的最有前途的饮食制剂之一；然而，黄酮类化合物，如槲皮素，其抗炎活性尚未完全确定，许多特性仍有待阐明。在本研究中，我们揭示了栎素下调TLR4信号转导的分子基础。Quercetin显著上调TLR信号的负调节因子Toll相互作用蛋白的表达。Quercetin抑制脂多糖诱导的细胞表面分子(CD80、CD86和MHC I/II类)的表达和促炎细胞因子(肿瘤坏死因子-α、IL-1β3、IL-6和IL-12p70)的产生，这种作用可被Toll相互作用蛋白沉默所阻止。此外，经栎素处理的巨噬细胞可抑制脂多糖诱导的丝裂原活化蛋白激酶，如细胞外信号调节蛋白1/2、p38和c-jun氨基末端激酶的激活，以及核因子-kappaB和p65通过Toll相互作用蛋白的转位。用槲皮素处理后，前列腺素E-2和环氧合酶-2水平以及内毒素诱导的诱导型一氧化氮合酶介导的一氧化氮生成均显著降低。综上所述，这些发现为理解TLR4信号通路的负调控机制和有效的炎症性疾病治疗干预提供了新的见解。(C)Elsevier Inc.出版的2013年。
Polyphenolic compounds have been regarded as one of the most promising dietary agents for the prevention and treatment of inflammation-related chronic diseases; however, the anti-inflammatory activities of flavonoids, such as quercetin, are not completely characterized, and many features remain to be elucidated. In this study, we showed the molecular basis for the downregulation of TLR4 signal transduction by quercetin. Quercetin markedly elevated the expression of the Toll-interacting protein, a negative regulator of TLR signaling. Lipopolysaccharide-induced expression of cell surface molecules (CD80, CD86, and MHC class I/II) and production of pro-inflammatory cytokines (tumor necrosis factor-alpha, IL-1 beta 3, IL-6, and IL-12p70) were inhibited by quercetin, and this action was prevented by Toll-interacting protein silencing. In addition, quercetin-treated macrophages inhibited lipopolysaccharide-induced activation of mitogen-activated protein kinases, such as extracellular signal-regulated kinase 1/2, p38, and c-Jun N-terminal kinase, and the translocation of nuclear factor-kappa B and p65 through Toll-interacting protein. Treatment with quercetin resulted in a significant decrease in prostaglandin E-2 and cyclooxygenase-2 levels as well as inducible nitric oxide synthase-mediated nitric oxide production induced by lipopolysaccharide. Taken together, these findings represent new insights into the understanding of negative regulatory mechanisms of the TLR4 signaling pathway and effective therapeutic intervention for the treatment of inflammatory disease. (C) 2013 Published by Elsevier Inc.