Isoacteoside, a dihydroxyphenylethyl glycoside, exhibits anti-inflammatory effects through blocking toll-like receptor 4 dimerization
Isoacteoside, a dihydroxyphenylethyl glycoside, exhibits anti-inflammatory effects through blocking toll-like receptor 4 dimerization
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DOI：
10.1111/bph.13912
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发表时间：
2017-09-01
影响因子：
7.3
通讯作者：
Chen, Xiuping
中科院分区：
文献类型：
--
作者：
Gao, Hongwei;Cui, Yankun;Chen, Xiuping
背景和用途异类升麻苷（是从Monochasma savatieri Franch. ex Maxim.中分离出来的一种苯乙醇，是一种广泛用于中药的抗炎草药。然而，异升麻苷抗炎活性的确切机制尚不完全清楚。在本研究中，阐明了其在小鼠巨噬细胞中的抗炎机制。实验方法NF-kappa B通路、MAPK的表达使用蛋白质印迹法评估 iNOS、TNF-α、IL-6 和 IL-1 beta，通过用 TLR4 质粒转染 HEK293T 细胞来测定 TLR4 二聚化。使用二甲苯诱导的耳水肿、LPS 诱导的内毒素休克和 LPS 诱导的内毒素血症相关急性肾损伤 (AKI) 小鼠模型测定异类升麻苷的体内抗炎作用。结果异类升麻苷可抑制COX-2、iNOS、TNF-α、IL-6 和IL-1β 的表达。此外，异升麻苷可通过降低磷酸化I kappa B-α 和IKK 以及NF-kappa B/p65 核转位的水平来减弱LPS 诱导的AP-1 转录活性。磷酸化 JNK1/2 和 p38MAPK 水平可阻断 LPS 诱导的 TLR4 二聚化，从而减少 MyD88 和含有 TIR 结构域的接头诱导干扰素 - β (TRIF) 的募集以及 TGF-β 激活激酶 - 1 (TAK1) 的磷酸化。结论和意义异类升麻苷可阻断 TLR4 二聚化，从而激活 MyD88-TAK1-NF-kappa B/MAPK 信号级联和 TRIF 通路。我们的数据表明，异升麻苷是治疗炎症性疾病的潜在先导化合物。
BACKGROUND AND PURPOSEIsoacteoside (is a phenylethanoid isolated from Monochasma savatieri Franch. ex Maxim., which is an anti-inflammatory herb widely used in traditional Chinese medicine. However, the exact mechanism of the anti-inflammatory activity of isoacteoside is not completely understood. In this study, its anti-inflammatory mechanism was elucidated in mouse macrophages.EXPERIMENTAL APPROACHThe expression of the NF-kappa B pathway, MAPK pathway, iNOS, TNF-alpha, IL-6 and IL-1 beta was evaluated using Western blotting, quantitative real-time PCR or ELISA. TLR4 dimerization was determined by transfecting HEK293T cells with TLR4 plasmids. The in vivo anti-inflammatory effect of isoacteoside was determined using mouse models of xylene-induced ear oedema, LPS-induced endotoxic shock and LPS-induced endotoxaemia-associated acute kidney injury (AKI).KEY RESULTSIsoacteoside suppressed COX-2, iNOS, TNF-alpha, IL-6 and IL-1 beta expression. Furthermore, isoacteoside attenuated the LPS-induced transcriptional activity of NF-kappa B by decreasing the levels of phosphorylated I kappa B-alpha and IKK and NF-kappa B/p65 nuclear translocation. In addition, isoacteoside inhibited LPS-induced transcriptional activity of AP-1 by reducing the levels of phosphorylated JNK1/2 and p38MAPK. Isoacteoside blocked LPS-induced TLR4 dimerization, resulting in a reduction in the recruitment of MyD88 and TIRdomain- containing adapter-inducing interferon-beta (TRIF) and the phosphorylation of TGF-beta-activated kinase-1 (TAK1). Pretreatment of mice with isoacteoside effectively inhibited xylene-induced ear oedema and LPS-induced endotoxic death and protected against LPS-induced AKI.CONCLUSIONS AND IMPLICATIONSIsoacteoside blocked TLR4 dimerization, which activates the MyD88-TAK1-NF-kappa B/MAPK signalling cascades and TRIF pathway. Our data indicate that isoacteoside is a potential lead compound for the treatment of inflammatory diseases.