Anti-inflammatory effects of Ang-(1-7) via TLR4-mediated inhibition of the JNK/FoxO1 pathway in lipopolysaccharide-stimulated RAW264.7 cells
Anti-inflammatory effects of Ang-(1-7) via TLR4-mediated inhibition of the JNK/FoxO1 pathway in lipopolysaccharide-stimulated RAW264.7 cells
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DOI：
10.1016/j.dci.2018.11.009
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发表时间：
2019-03-01
影响因子：
2.9
通讯作者：
Tang, Lin
中科院分区：
文献类型：
--
作者：
Jiang, Mei;Huang, Wenhan;Tang, Lin
针对炎症被认为是预防或延缓炎症性疾病（例如严重哮喘、克罗恩病和类风湿性关节炎）发展的具有挑战性的药理学策略。血管紧张素-(1-7)-Mas轴((Ang-(1-7)-Mas axis)被证实可以拮抗血管紧张素受体轴的作用，据报道血管紧张素受体轴可以调节心血管和肾功能，并有助于炎症过程。在本文中，我们旨在探讨Ang-(1-7)在炎症中的关键作用，并揭示脂多糖(LPS)诱导的小鼠巨噬细胞的机制RAW264.7.我们发现Ang-(1-7)以浓度依赖性方式抑制LPS诱导的巨噬细胞中肿瘤坏死因子-α和白细胞介素-6的产生和分泌，LPS诱导的TLR4、磷酸-JNK和FoxO1的过度表达也通过与Ang-(1-7)一起孵育而被抑制。此外，我们还使用了选择性JNK抑制剂来逆转这些抑制作用。 Sp600125进一步证实TLR4、JNK和FoxO1参与Ang-(1-7)的抗炎作用我们的研究揭示了Ang(1-7)可能通过抑制LPS诱导的巨噬细胞中TLR4介导的JNK/FoxO1信号通路来驱动抗炎作用的新机制。
Targeting inflammation is considered a challenging pharmacological strategy to prevent or delay the development of inflammatory diseases, such as severe asthma, Crohn's disease, and rheumatoid arthritis. The angiotensin-(1-7) -Mas axis ((Ang-(1-7)-Mas axis) was confirmed to antagonize the effects of the Angiotensin receptor axis and the latter is reported to regulate cardiovascular and renal function, as well as contribute to the inflammatory process. In this paper, we aim to explore the crucial effect of Ang-(1-7) in inflammation and disclose the mechanisms in lipopolysaccharide (LPS)-induced murine macrophages RAW264.7. We found that Ang-(1-7) inhibited the production and secretion of tumor necrosis factor-alpha and interleukin-6 in a concentration-dependent manner in LPS-induced macrophages. The overexpression of TLR4, phospho-JNK, and FoxO1 induced by LPS were also inhibited by incubation with Ang-(1-7). These inhibitory effects were reversed by A779. Moreover, we also used a selective JNK inhibitor Sp600125 to further corroborate the involvement of TLR4, JNK, and FoxO1 in the anti-inflammatory action of Ang-(1-7). Our research reveals a new mechanism that Ang(1-7) may drive anti-inflammatory effects via the Mas receptor through inhibition of the TLR4-mediated JNK/FoxO1 signaling pathway in LPS-induced macrophages. Our findings open new perspectives of Ang-(1-7)-Mas axis in local inflammation.