阿齐沙坦通过抑制氧化应激和抑制TLR2 / MyD88信号通路抑制U937巨噬细胞中LPS诱导的炎症,ACS Omega

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阿齐沙坦通过抑制氧化应激和抑制TLR2 / MyD88信号通路抑制U937巨噬细胞中LPS诱导的炎症
ACS Omega ( IF 3.7 ) Pub Date : 2020-12-21 , DOI: 10.1021/acsomega.0c03655
Qinglian Dong ₁ , Yongxia Li ₂ , Juan Chen ₁ , Nan Wang ₃

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背景与目的：脂多糖（LPS）是引起严重炎症，导致多种疾病的重要因素。据报道，LPS诱导的炎症与NF-κB信号通路的活化和活性氧（ROS）诱导的氧化应激有关。阿兹沙坦是一种血管紧张素II型（AT1）受体阻滞剂，已被许可用作新一代的Sartan降压药。但是，阿兹沙坦对LPS诱导的炎症的作用尚未见报道。本研究旨在研究阿扎西坦对脂多糖刺激的巨噬细胞的抗炎作用，并探讨其潜在机制。方法：释放乳酸脱氢酶（LDH），分泌HMGB-1以及IL-6，IL-1β，MCP-1，MMP-2，MMP-9和PGE _2的浓度使用酶联免疫吸附测定法（ELISA）进行免疫评估。通过定量逆转录聚合酶链反应（qRT-PCR）确定IL-6，IL-1β，MCP-1，MMP-2，MMP-9和COX-2的基因表达水平。蛋白质印迹分析用于检测COX-2，Nrf2，TLR2，MyD-88和NF-κB的蛋白表达水平。使用二氢乙锭（DHE）染色测定法确定ROS的水平。使用荧光素酶活性测定法评估NF-κB的活性。结果：LDH，HMGB-1，IL-6，IL-1β，MCP-1，MMP-2，MMP-9和PGE ₂释放LPS刺激可显着促进其被激活，而阿齐沙坦可显着抑制它。阿兹沙坦显着下调了LPS处理的巨噬细胞中COX-2，TLR2，MyD-88和NF-κB的上调。有趣的是，Azilsartan提高了Nrf2的表达水平。相反，LPS大大提高了ROS水平，但阿齐沙坦抑制了ROS水平。从机理上，发现阿齐沙坦抑制了LPS诱导的TLR2 / Myd-88 /NF-κB信号通路的激活。结论：阿齐沙坦可能通过抑制氧化应激和抑制TLR / MyD88信号通路来抑制LPS诱导的U937巨噬细胞炎症。

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Azilsartan Suppressed LPS-Induced Inflammation in U937 Macrophages through Suppressing Oxidative Stress and Inhibiting the TLR2/MyD88 Signal Pathway

Background and purpose: Lipopolysaccharide (LPS) is an important factor that induce severe inflammation, resulting in multiple types of diseases. It is reported that LPS-induced inflammation is related to the activation of the NF-κB signal pathway and reactive oxygen species (ROS)-induced oxidative stress. Azilsartan, an angiotensin II type 1 (AT1) receptor blocker, has been licensed as a new generation of Sartan antihypertensive drugs. However, the effects of azilsartan in LPS-induced inflammation have not been reported before. The present study aims to investigate the anti-inflammatory effects of azilsartan on LPS-stimulated macrophages and explore the underlying mechanism. Methods: The release of lactic dehydrogenase (LDH), secretion of HMGB-1, and concentrations of IL-6, IL-1β, MCP-1, MMP-2, MMP-9, and PGE₂ were evaluated using the enzyme-linked immunosorbent assay (ELISA). The gene expression levels of IL-6, IL-1β, MCP-1, MMP-2, MMP-9, and COX-2 were determined by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Western blot analysis was used to detect the protein expression level of COX-2, Nrf2, TLR2, MyD-88, and NF-κB. The level of ROS was determined using the dihydroethidium (DHE) staining assay. The activity of NF-κB was evaluated using the luciferase activity assay. Results: The release of LDH, HMGB-1, IL-6, IL-1β, MCP-1, MMP-2, MMP-9, and PGE₂ was significantly promoted by LPS stimulation, whereas it was greatly suppressed by azilsartan. The upregulated COX-2, TLR2, MyD-88, and NF-κB in the LPS-treated macrophages were significantly downregulated by azilsartan. Interestingly, the expression level of Nrf2 was elevated by azilsartan. On the contrary, ROS levels were greatly increased by LPS but suppressed by azilsartan. Mechanistically, it was found that azilsartan suppressed LPS-induced activation of the TLR2/Myd-88/NF-κB signaling pathway. Conclusion: Azilsartan might suppress LPS-induced inflammation in U937 macrophages through suppressing oxidative stress and inhibiting the TLR/MyD88 signal pathway.

更新日期：2021-01-12

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