Li De-Chuan, Bao Xiu-Qi, Wang Xiao-Liang, Sun Hua, Zhang Dan
State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, China.
Beijing Institute for Brain Disorders, 10 Xitoutiao, Youanmen Wai, Beijing, 100054, China.
Naunyn Schmiedebergs Arch Pharmacol. 2017 Jun;390(6):643-650. doi: 10.1007/s00210-017-1363-6. Epub 2017 Mar 9.
High mobility group box 1 (HMGB1) is a critical pro-inflammatory cytokine that contributes to the pathogenesis of various human diseases. FLZ, a squamosamide derivative, has been demonstrated to have neuroprotective effects in Parkinson's disease models and shows strong anti-inflammatory activity, while the precise mechanism remains unclear. Here, we investigated the anti-inflammatory mechanism of FLZ on HMGB1-mediated inflammatory responses. The effects of FLZ on HMGB1 release from microglial cells induced by lipopolysaccharide were first explored by Western blot assay and ELISA. Then, co-immunoprecipition was used to study FLZ's effect on the interaction between HMGB1 and its receptor TLR4. Finally, we employed HMGB1 to simulate pro-inflammatory responses and then studied the inhibitory effects of FLZ on its bioactivity. FLZ has a significant inhibitory effect on HMGB1 release while it exerts no inhibitory effect on the binding between HMGB1 and TLR4. After the recognition of HMGB1 by TLR4, NF-κB signaling pathway is activated. FLZ could efficaciously alleviate HMGB1-induced inflammatory responses via the suppression of TLR4/MyD88/NF-κB signaling pathway. FLZ could inhibit HMGB1 release as well as HMGB1-induced inflammatory responses, HMGB1 might be one of the FLZ anti-inflammatory targets, and interfering at this inflammatory mediator may have benefit effects on neurodegenerative disorders, such as Parkinson's disease.
高迁移率族蛋白B1（HMGB1）是一种关键的促炎细胞因子，在多种人类疾病的发病机制中起作用。FLZ是一种鳞酰胺衍生物，已被证明在帕金森病模型中具有神经保护作用，并表现出强大的抗炎活性，但其确切机制仍不清楚。在此，我们研究了FLZ对HMGB1介导的炎症反应的抗炎机制。首先通过蛋白质免疫印迹分析和酶联免疫吸附测定法探究了FLZ对脂多糖诱导的小胶质细胞释放HMGB1的影响。然后，采用免疫共沉淀法研究FLZ对HMGB1与其受体TLR4之间相互作用的影响。最后，我们用HMGB1模拟促炎反应，进而研究FLZ对其生物活性的抑制作用。FLZ对HMGB1的释放具有显著抑制作用，而对HMGB1与TLR4之间的结合没有抑制作用。在TLR4识别HMGB1后，核因子κB信号通路被激活。FLZ可通过抑制TLR4/髓样分化因子88/核因子κB信号通路有效减轻HMGB1诱导的炎症反应。FLZ可抑制HMGB1的释放以及HMGB1诱导的炎症反应，HMGB1可能是FLZ的抗炎靶点之一，干扰这种炎症介质可能对神经退行性疾病如帕金森病具有有益作用。
