Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; Department of Pharmacy, The Third People's Hospital of Wuxi, Wuxi, Jiangsu, 214000, China.
Toxicol Lett. 2019 May 15;306:53-60. doi: 10.1016/j.toxlet.2019.02.005. Epub 2019 Feb 12.
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-β-activated kinase-1 (TAK1) phosphorylation with subsequent activation of nuclear factor-κB (NF-κB). KPF attenuates LPS-mediated production of cytokines as well as activation of NF-κB. 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.
急性肺损伤（ALI）及其严重形式，急性呼吸窘迫综合征（ARDS），是一个主要的临床挑战。该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）可降低小鼠内毒素诱导的炎症反应。然而，这些抗炎活性的机制目前尚不清楚。在这里，我们表明，脂多糖（LPS）刺激下炎症细胞因子的产生增加是由于转化生长因子-β激活激酶-1（TAK1）的磷酸化增加，随后核因子-κB（NF-κB）的激活。KPF 可减轻 LPS 介导的细胞因子产生以及 NF-κB 的激活。此外，我们发现 KPF 可防止肿瘤坏死因子受体相关因子 6（TRAF6）和白细胞介素 1 受体相关激酶 1（IRAK1）上 K63 连接的多泛素化增加。K63 连接的多泛素化是导致包括 TAK1 在内的下游途径激活增强的信号。我们的研究表明，KPF 通过调节 TRAF6 多泛素化可有效减轻 LPS 诱导的肺损伤。此外，我们的发现可能为减轻急性肺损伤提供新的分子靶点。
