A novel chromone derivative with anti-inflammatory property via inhibition of ROS-dependent activation of TRAF6-ASK1-p38 pathway.
A novel chromone derivative with anti-inflammatory property via inhibition of ROS-dependent activation of TRAF6-ASK1-p38 pathway.
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一种新型色酮衍生物，通过抑制 TRAF6-ASK1-p38 通路的 ROS 依赖性激活而具有抗炎特性
DOI：
10.1371/journal.pone.0037168
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Xu Q
中科院分区：
文献类型：
--
作者：
Liu H;Xu R;Feng L;Guo W;Cao N;Qian C;Teng P;Wang L;Wu X;Sun Y;Li J;Shen Y;Xu Q
p38 MAPK信号通路在炎症中起着关键作用。靶向p38 MAPK可能是治疗炎症性疾病的潜在策略。在本研究中，我们发现一种新的色酮衍生物，DCO-6，显着减少脂多糖（LPS）诱导的一氧化氮，IL-1β和IL-6的产生，降低iNOS，IL-1 β和IL-6的mRNA表达水平在RAW 264.7细胞和小鼠原代腹腔巨噬细胞，并抑制LPS诱导的p38 MAPK的激活，但不抑制JNK，ERK。此外，DCO-6特异性抑制TLR 4依赖性p38活化，而不直接抑制其激酶活性。DCO-6可显著抑制LPS诱导的细胞内活性氧（ROS）的产生，破坏TRAF 6-ASK 1复合物的形成。施用DCO-6显著保护小鼠免受LPS诱导的脓毒性休克，同时抑制p38活化和ROS产生。我们的研究结果表明，DCO-6通过抑制TRAF 6-ASK 1-p38通路的ROS依赖性激活而显示出抗炎特性。通过DCO-6阻断p38 MAPK作用所需的上游事件可能为炎症性疾病的治疗提供新的治疗选择。
The p38 MAPK signaling pathway plays a pivotal role in inflammation. Targeting p38 MAPK may be a potential strategy for the treatment of inflammatory diseases. In the present study, we show that a novel chromone derivative, DCO-6, significantly reduced lipopolysaccharide (LPS)-induced production of nitric oxide, IL-1β and IL-6, decreased the levels of iNOS, IL-1β and IL-6 mRNA expression in both RAW264.7 cells and mouse primary peritoneal macrophages, and inhibited LPS-induced activation of p38 MAPK but not of JNK, ERK. Moreover, DCO-6 specifically inhibited TLR4-dependent p38 activation without directly inhibiting its kinase activity. LPS-induced production of intracellular reactive oxygen species (ROS) was remarkably impaired by DCO-6, which disrupted the formation of the TRAF6-ASK1 complex. Administering DCO-6 significantly protected mice from LPS-induced septic shock in parallel with the inhibition of p38 activation and ROS production. Our results indicate that DCO-6 showed anti-inflammatory properties through inhibition of ROS-dependent activation of TRAF6-ASK1-p38 pathway. Blockade of the upstream events required for p38 MAPK action by DCO-6 may provide a new therapeutic option in the treatment of inflammatory diseases.
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