MLN4924 protects against interleukin-17A-induced pulmonary inflammation by disrupting ACT1-mediated signaling
MLN4924 protects against interleukin-17A-induced pulmonary inflammation by disrupting ACT1-mediated signaling
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MLN4924 通过破坏 ACT1 介导的信号传导来防止白细胞介素 17A 诱导的肺部炎症
DOI：
10.1152/ajplung.00349.2018
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发表时间：
2019-06-01
影响因子：
4.9
通讯作者：
Sun, Lei
中科院分区：
文献类型：
--
作者：
Hao, Rui;Song, Yunduan;Sun, Lei
终端气道过度炎症反应。肺动脉高压和慢性阻塞性肺疾病是由肺动脉高压引起的。促炎细胞因子白细胞介素-17A（IL-17 A）参与了肺部炎症性疾病的发病机制。MLN 4924是一种NEDD 8激活酶（NAE）抑制剂，与各种类型癌症的治疗相关，但其在IL-17 A介导的炎症反应中的作用尚未确定。在此，我们报告了MLN 4924可显著降低IL-17 A腺病毒诱导的肺部炎症小鼠模型中促炎细胞因子和趋化因子（如IL-1 β、IL-6和CXCL-1）的表达以及嗜中性粒细胞。MLN 4924在体外显著抑制IL-17 A诱导的促炎细胞因子和趋化因子mRNA稳定。机械地。MLN 4924可显著阻断MAPK和NF-κ B通路的激活，并干扰ACTI和肿瘤坏死因子受体相关因子蛋白（TRAF）之间的相互作用，从而抑制TRAF 6泛素化。综上所述，我们的数据揭示了MLN 4924对IL-17 A介导的炎症反应的先前未表征的抑制作用;该现象可能有助于MLN 4924开发为治疗肺部炎症性疾病的有效小分子药物。
An excessive inflammatory response in terminal airways. alveoli, and the lung interstitium eventually leads to pulmonary hypertension and chronic obstructive pulmonary disease. Proinflammatory cytokine interleukin-17A (IL-17A) has been implicated in the pathogenesis of pulmonary inflammatory diseases. MLN4924, an inhibitor of NEDD8-activating enzyme (NAE), is associated with the treatment of various types of cancers, but its role in the IL-17A-mediated inflammatory response has not been identified. Here, we report that MLN4924 can markedly reduce the expression of proinflammatory cytokines and chemokines such as IL-1 beta, IL-6, and CXCL-1 and neutrophilia in a mouse model of IL-17A adenovirus-induced pulmonary inflammation. MLN4924 significantly inhibited IL-17A-induced stabilization of mRNA of proinflammatory cytokines and chemokines in vitro. Mechanistically. MLN4924 significantly blocked the activation of MAPK and NF-kappa B pathways and interfered with the interaction between ACTI and tumor necrosis factor receptor-associated factor proteins (TRAFs), thereby inhibiting TRAF6 ubiquitination. Taken together, our data uncover a previously uncharacterized inhibitory effect of MLN4924 on the IL-17A-mediated inflammatory response; this phenomenon may facilitate the development of MLN4924 into an effective small-molecule drug for the treatment of pulmonary inflammatory diseases.