Kaempferol reduces K63-linked polyubiquitination to inhibit nuclear factor-κB and inflammatory responses in acute lung injury in mice
Kaempferol reduces K63-linked polyubiquitination to inhibit nuclear factor-κB and inflammatory responses in acute lung injury in mice
复制标题
山奈酚减少 K63 连接的多聚泛素化，抑制小鼠急性肺损伤中的核因子-κ B 和炎症反应
DOI：
10.1016/j.toxlet.2019.02.005
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发表时间：
2019-05-15
影响因子：
3.5
通讯作者：
Zheng, Chao
中科院分区：
文献类型：
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作者：
Qian, Jianchang;Chen, Xuemei;Zheng, Chao
急性肺损伤（ALI）及其严重形式急性呼吸窘迫综合征（ARDS）构成了一个重大的临床挑战。这种综合征的主要驱动力是肺部炎症。最近的研究表明，天然存在的类黄酮山奈酚（KPF）减少内毒素诱导的小鼠炎症反应。然而，这些抗炎活性的机制目前尚不清楚。在这里，我们表明，增强炎症细胞因子的生产响应脂多糖（LPS）是由于增加TGF-β激活激酶1（TAK 1）磷酸化，随后激活核因子-κ B（NF-κ B）。KPF减弱LPS介导的细胞因子产生以及NF-κ B活化。此外，我们还发现KPF可以阻止TNF受体相关因子6（TRAF 6）和白细胞介素1受体相关激酶1（IRAK 1）上K63连接的多聚泛素化。K63连接的多聚泛素化是导致包括TAK 1在内的下游途径活化增强的信号。我们的研究表明，KPF通过调节TRAF 6多聚泛素化而有效减轻LPS诱导的肺损伤。此外，我们的研究结果可能提供新的分子靶点，以减轻急性肺损伤。
Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), pose a major clinical challenge. The major driving force in this syndrome is pulmonary inflammation. Recent studies have shown that the naturally occurring flavonoid kaempferol (KPF) reduces endotoxin-induced inflammatory responses in mice. However, the mechanisms of these anti-inflammatory activities are not currently known. Here, we show that enhanced inflammatory cytokine production in response to lipopolysaccharide (LPS) is due to increased TGF-beta-activated kinase-1 (TAK1) phosphorylation with subsequent activation of nuclear factor-kappa B (NF-kappa B). KPF attenuates LPS-mediated production of cytokines as well as activation of NF-kappa B. Furthermore, we identified that KPF prevents increased K63-linked polyubiquitination on TNF receptor associated factor-6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1). K63-linked polyubiquitination is a signal leading to enhanced activation of downstream pathways including TAK1. Our study shows that KPF is effective in reducing lung damage induced by LPS by modulating TRAF6 polyubiquitination. Furthermore, our findings may provide novel molecular targets to alleviate acute lung injury.