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首页> 外文期刊>Molecular and Cellular Biology >Phosphoinositide-Dependent Kinase 1 Provides Negative Feedback Inhibition to Toll-Like Receptor-Mediated NF-κB Activation in Macrophages
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Phosphoinositide-Dependent Kinase 1 Provides Negative Feedback Inhibition to Toll-Like Receptor-Mediated NF-κB Activation in Macrophages

机译：磷酸肌醇依赖性激酶1对巨噬细胞中的类似受体介导的NF-κB活化提供负反馈抑制作用。

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摘要

Phosphoinositide-dependent kinase 1 (PDK-1) represents an important signaling component in the phosphatidylinositol 3-kinase (PI3K) pathway, which plays an essential role in controlling a coordinated innate immune response. Here, we show that mice with conditional disruption of PDK-1 specifically in myeloid lineage cells (PDK-1Δmyel mice) show enhanced susceptibility to lipopolysaccharide (LPS)-induced septic shock accompanied by exaggerated liver failure. Furthermore, primary macrophages derived from PDK-1Δmyel mice lack LPS- and Pam3CSK4-stimulated AKT activity but exhibit increased mRNA expression and release of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). Moreover, LPS- and Pam3CSK4-stimulated primary macrophages exhibit enhanced phosphorylation and degradation of IκBα. While immediate upstream Toll-like receptor 4 (TLR-4)-induced signaling, including IL-1 receptor (IL-1R)-associated protein kinase (IRAK) phosphorylation, is unaltered in the absence of PDK-1, macrophages from PDK-1Δmyel mice exhibit prolonged ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF-6) in response to LPS stimulation. These experiments reveal a novel PDK-1-dependent negative feedback inhibition of TLR-induced NF-κB activation in macrophages in vivo.
机译：磷脂酰肌醇依赖性激酶1（PDK-1）代表磷脂酰肌醇3-激酶（PI3K）途径中的重要信号传导成分，在控制协调的先天免疫应答中起着至关重要的作用。在这里，我们显示了在髓系谱系细胞中有条件地破坏PDK-1的小鼠（PDK-1 Δmyel小鼠）显示出对脂多糖（LPS）引起的败血性休克的敏感性增加，并伴有肝功能衰竭。此外，衍生自PDK-1 Δmyel小鼠的原代巨噬细胞缺乏LPS-和Pam3CSK4刺激的AKT活性，但mRNA表达增加，并释放肿瘤坏死因子α（TNF-α）和白介素6（IL- 6）。此外，LPS和Pam3CSK4刺激的初级巨噬细胞表现出增强的IκBα磷酸化和降解。在缺乏PDK-1的情况下，直接上游Toll样受体4（TLR-4）诱导的信号转导，包括与IL-1受体（IL-1R）相关的蛋白激酶（IRAK）磷酸化，却没有改变，而来自PDK- 1 Δmyel小鼠响应LPS刺激，其肿瘤坏死因子受体相关因子6（TRAF-6）的泛素化时间延长。这些实验揭示了一种新的PDK-1依赖性负反馈抑制TLR诱导的巨噬细胞在体内的激活。

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