Glycyrrhizin and isoliquiritigenin suppress the LPS sensor Toll-like receptor 4/MD-2 complex signaling in a different manner
Glycyrrhizin and isoliquiritigenin suppress the LPS sensor Toll-like receptor 4/MD-2 complex signaling in a different manner
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DOI：
10.1189/jlb.0112038
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发表时间：
2012-06-01
影响因子：
5.5
通讯作者：
Takatsu, Kiyoshi
中科院分区：
文献类型：
--
作者：
Honda, Hiroe;Nagai, Yoshinori;Takatsu, Kiyoshi
最近的研究表明，植物提取物能够调节天然免疫反应。皂苷GL和查耳酮ILG是甘草的代表性组分，其减弱由TLR介导的炎症反应。在这里，我们表明，GL和ILG抑制LPS传感器TLR 4/MD-2复合物信号在受体水平的不同步骤。提取物G.乌拉尔甘草抑制LPS的脂质A部分诱导的RAW 264.7细胞中IL-6和TNF-α的产生。在各种G.甘草酸中毒相关成分皂苷和黄烷酮/查尔酮、GL和ILG可以剂量依赖性地抑制脂质A诱导的RAW264.7细胞产生IL-6。此外，被动给予GL或ILG可减弱LPS注射小鼠血浆TNF-α的升高。GL和ILG抑制脂质A诱导的表达TLR 4/MD-2和CD 14和BNF的Ba/F3细胞中NF-κ B B活化。这些成分也抑制MAPK的活化，包括JNK，p38和ERK在BERK中。此外，GL和ILG抑制NF-κ B活化和由紫杉醇（一种非细菌性TLR 4配体）诱导的IL-6产生。有趣的是，GL减弱了LPS-TLR 4/MD-2复合物的形成，导致TLR 4的同源二聚化的抑制。虽然ILG不影响LPS与TLR 4/MD-2的结合，但它可以抑制LPS诱导的TLR 4同源二聚化。这些结果意味着GL和ILG在受体水平调节TLR 4/MD-2复合物，导致抑制LPS诱导的信号级联激活和细胞因子产生，但它们的作用在TLR 4/MD-2信号传导的不同步骤中发挥。J. Leukoc. 91：967-976; 2012.
Recent evidences suggest that the extracts of plant products are able to modulate innate immune responses. A saponin GL and a chalcone ILG are representative components of Glycyrrhiza uralensis, which attenuate inflammatory responses mediated by TLRs. Here, we show that GL and ILG suppress different steps of the LPS sensor TLR4/MD-2 complex signaling at the receptor level. Extract of G. uralensis suppressed IL-6 and TNF-alpha production induced by lipid A moiety of LPS in RAW264.7 cells. Among various G. uralensis-related components of saponins and flavanones/chalcones, GL and ILG could suppress IL-6 production induced by lipid A in dose-dependent manners in RAW264.7 cells. Furthermore, elevation of plasma TNF-alpha in LPS-injected mice was attenuated by passive administration of GL or ILG. GL and ILG inhibited lipid A-induced NF-kappa B activation in Ba/F3 cells expressing TLR4/MD-2 and CD14 and BMMs. These components also inhibited activation of MAPKs, including JNK, p38, and ERK in BMMs. In addition, GL and ILG inhibited NF-kappa B activation and IL-6 production induced by paclitaxel, a nonbacterial TLR4 ligand. Interestingly, GL attenuated the formation of the LPS-TLR4/MD-2 complexes, resulting in inhibition of homodimerization of TLR4. Although ILG did not affect LPS binding to TLR4/MD-2, it could inhibit LPS-induced TLR4 homodimerization. These results imply that GL and ILG modulate the TLR4/MD-2 complex at the receptor level, leading to suppress LPS-induced activation of signaling cascades and cytokine production, but their effects are exerted at different steps of TLR4/MD-2 signaling. J. Leukoc. Biol. 91: 967-976; 2012.