ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity
ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity
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DOI：
10.1038/ni1200
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发表时间：
2005-06-01
影响因子：
30.5
通讯作者：
Ichijo, H
中科院分区：
文献类型：
--
作者：
Matsuzawa, A;Saegusa, K;Ichijo, H
凋亡信号调节激酶1（ASK 1）是一种进化上保守的丝裂原活化蛋白3激酶，其激活JNK和p38丝裂原活化蛋白激酶。在这里，我们使用ASK 1缺陷小鼠，以表明ASK 1是脂多糖诱导的p38激活所选择性需要的，而不是JNK或转录因子NF-κ B。ASK 1是诱导依赖于Toll样受体4（TLR 4）而不是TLR 2或其他TLRs的促炎细胞因子所必需的。与此一致，ASK 1缺陷小鼠对脂多糖诱导的脓毒性休克具有抗性。脂多糖诱导细胞内活性氧的产生，这是形成接头分子TRAF 6和ASK 1的复合物以及随后激活ASK 1-p38通路所必需的。我们的数据表明活性氧依赖性TRAF 6-ASK 1-p38轴对TLR 4介导的哺乳动物先天免疫至关重要。
Apoptosis signal - regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein 3-kinase that activates both Jnk and p38 mitogen-activated protein kinases. Here we used ASK1-deficient mice to show that ASK1 was selectively required for lipopolysaccharide-induced activation of p38 but not of Jnk or the transcription factor NF-kappa B. ASK1 was required for the induction of proinflammatory cytokines dependent on Toll-like receptor 4 (TLR4) but not TLR2 or other TLRs. Consistent with this, ASK1-deficient mice were resistant to lipopolysaccharide-induced septic shock. Lipopolysaccharide induced the production of intracellular reactive oxygen species, which was required for the formation of a complex of the adaptor molecule TRAF6 and ASK1 and subsequent activation of the ASK1-p38 pathway. Our data demonstrate that the reactive oxygen species - dependent TRAF6-ASK1-p38 axis is crucial for TLR4-mediated mammalian innate immunity.