Imperatorin Interferes with LPS Binding to the TLR4 Co-Receptor and Activates the Nrf2 Antioxidative Pathway in RAW264.7 Murine Macrophage Cells.
Imperatorin Interferes with LPS Binding to the TLR4 Co-Receptor and Activates the Nrf2 Antioxidative Pathway in RAW264.7 Murine Macrophage Cells.
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DOI：
10.3390/antiox10030362
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发表时间：
2021-02-27
期刊：
影响因子：
--
通讯作者：
Hsieh WT
中科院分区：
文献类型：
--
作者：
Huang MH;Lin YH;Lyu PC;Liu YC;Chang YS;Chung JG;Lin WY;Hsieh WT
欧前胡素（IMP）可下调多种炎症转录因子信号通路。有研究指出IMP可干扰Toll样受体4（TLR 4）信号通路。本研究通过蛋白质-配体对接模型、蛋白质印迹、免疫荧光（IF）和原子力显微镜（AFM）分析，在脂多糖（LPS）刺激的巨噬细胞样RAW264.7细胞中评估IMP如何干扰TLR 4共受体信号传导。蛋白-配体对接的结果表明，IMP干扰LPS刺激的RAW 264.7细胞中LPS结合LPS结合蛋白（LBP）、分化簇14（CD 14）和toll样受体4/髓样分化因子2（TLR 4/MD-2）共受体。与TLR 4拮抗剂CLI-095或地塞米松相比，IMP可抑制LPS刺激的细胞LBP、CD 14和TLR 4/MD-2蛋白表达。AFM三维图像分析显示IMP对LPS诱导的RAW264.7细胞形态学改变有抑制作用。此外，IMP还能激活核因子红细胞2相关因子2（Nrf 2）信号通路，增加血红素加氧酶-1（HO-1）、超氧化物歧化酶（SOD）和过氧化氢酶（CAT）等抗氧化蛋白的表达。我们的研究结果首次揭示了IMP的抗炎作用干扰了LPS与TLR 4共受体信号的结合，并激活了抗氧化Nrf 2信号通路。
Imperatorin (IMP) could downregulate several inflammatory transcription factor signaling pathways. Some studies have pointed out that IMP could interfere with toll-like receptor 4 (TLR4) signaling. This study evaluates how IMP interferes with the TLR4 co-receptors signaling through the protein-ligand docking model, Western blotting, immunofluorescence (IF), and atomic force microscopy (AFM) assays in lipopolysaccharide (LPS) stimulated macrophage-like RAW264.7 cells in vitro. The results of the protein-ligand docking demonstrate that IMP interferes with LPS binding to the LPS-binding protein (LBP), the cluster of differentiation 14 (CD14), and the toll-like receptor 4/myeloid differentiation factor 2 (TLR4/MD-2) co-receptors in LPS-stimulated RAW264.7 cells. Compared with TLR4 antagonist CLI-095 or dexamethasone, IMP could suppress the protein expressions of LBP, CD14, and TLR4/MD-2 in LPS-stimulated cells. Furthermore, the three-dimensional (3D) image assay of the AFM showed IMP could prevent the LPS-induced morphological change in RAW264.7 cells. Additionally, IMP could activate the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, and it increased the antioxidative protein expression of heme oxygenase-1 (HO-1), superoxidase dismutase (SOD), and catalase (CAT). Our results are the first to reveal that the anti-inflammatory effect of IMP interferes with LPS binding to TLR4 co-receptor signaling and activates the antioxidative Nrf2 signaling pathway.
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