Phosphoinositide-Dependent Kinase 1 Provides Negative Feedback Inhibition to Toll-Like Receptor-Mediated NF-κB Activation in Macrophages
Phosphoinositide-Dependent Kinase 1 Provides Negative Feedback Inhibition to Toll-Like Receptor-Mediated NF-κB Activation in Macrophages
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DOI：
10.1128/mcb.00069-10
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发表时间：
2010-09-01
影响因子：
5.3
通讯作者：
Bruening, Jens C.
中科院分区：
文献类型：
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作者：
Chaurasia, Bhagirath;Mauer, Jan;Bruening, Jens C.
磷酸肌醇依赖性激酶 1 (PDK-1) 代表磷脂酰肌醇 3 激酶 (PI3K) 通路中的重要信号成分，在控制协调的先天免疫反应中发挥着重要作用。在这里，我们发现，特别是在骨髓谱系细胞中条件性破坏 PDK-1 的小鼠（PDK-1(Delta myel) 小鼠）表现出对脂多糖 (LPS) 诱导的败血性休克的易感性增强，并伴有严重的肝衰竭。此外，源自 PDK-1(Delta myel) 小鼠的原代巨噬细胞缺乏 LPS 和 Pam3CSK4 刺激的 AKT 活性，但表现出 mRNA 表达增加以及肿瘤坏死因子 α (TNF-α) 和白细胞介素 6 (IL-6) 的释放。此外，LPS 和 Pam3CSK4 刺激的初级巨噬细胞表现出 I kappa B α 的磷酸化和降解增强。虽然直接上游 Toll 样受体 4 (TLR-4) 诱导的信号转导，包括 IL-1 受体 (IL-1R) 相关蛋白激酶 (IRAK) 磷酸化，在没有 PDK-1 的情况下不会改变，但 PDK-1(Delta myel) 小鼠的巨噬细胞响应 LPS 刺激，表现出肿瘤坏死因子受体相关因子 6 (TRAF-6) 的长时间泛素化。这些实验揭示了体内巨噬细胞中 TLR 诱导的 NF-κ B 激活的新型 PDK-1 依赖性负反馈抑制。
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-1(Delta myel) mice) show enhanced susceptibility to lipopolysaccharide (LPS)-induced septic shock accompanied by exaggerated liver failure. Furthermore, primary macrophages derived from PDK-1(Delta myel) mice lack LPS- and Pam3CSK4-stimulated AKT activity but exhibit increased mRNA expression and release of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). Moreover, LPS- and Pam3CSK4-stimulated primary macrophages exhibit enhanced phosphorylation and degradation of I kappa B alpha. 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-1(Delta myel) 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-kappa B activation in macrophages in vivo.