Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling.
Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling.
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DOK-1和DOK-2是脂多糖诱导的信号传导的负调节剂。
DOI：
10.1084/jem.20041817
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发表时间：
2005-02-07
期刊：
影响因子：
--
通讯作者：
Yamanashi Y
中科院分区：
文献类型：
--
作者：
Shinohara H;Inoue A;Toyama-Sorimachi N;Nagai Y;Yasuda T;Suzuki H;Horai R;Iwakura Y;Yamamoto T;Karasuyama H;Miyake K;Yamanashi Y
内毒素是一种细菌脂多糖（LPS），通过巨噬细胞等先天免疫效应细胞上的Toll样受体（TLR）4引起致死性脓毒性休克，在巨噬细胞上，它激活核因子κB（NF-κB）和丝裂原活化蛋白（MAP）激酶以诱导促炎性细胞因子如肿瘤坏死因子（TNF）-α。Dok-1和Dok-2是负调节蛋白酪氨酸激酶（PTK）下游的Ras-Erk信号传导的衔接蛋白。在这里，我们证明，LPS迅速诱导这些蛋白质的酪氨酸磷酸化和衔接功能。LPS刺激Dok-1或Dok-2缺失小鼠巨噬细胞可诱导Erk活化升高，但其他MAP激酶或NF-κB不升高，导致TNF-α和一氧化氮的过度产生。此外，突变小鼠表现出TNF-α的过度产生和对LPS的超敏反应。然而，从这些突变小鼠的巨噬细胞反应正常的其他致病分子，CpG寡脱氧核苷酸，聚（I：C）核糖核苷酸，或Pam 3CSK 4脂肽，激活同源TLR，但诱导没有酪氨酸磷酸化的Dok-1或Dok-2。在巨噬细胞中强制表达任一衔接子，但不表达具有Tyr/Phe取代的突变体，抑制LPS诱导的Erk活化和TNF-α产生。因此，Dok-1和Dok-2是TLR 4下游的重要负调节因子，这意味着先天免疫中的新的PTK依赖性途径。
Endotoxin, a bacterial lipopolysaccharide (LPS), causes fatal septic shock via Toll-like receptor (TLR)4 on effector cells of innate immunity like macrophages, where it activates nuclear factor κB (NF-κB) and mitogen-activated protein (MAP) kinases to induce proinflammatory cytokines such as tumor necrosis factor (TNF)-α. Dok-1 and Dok-2 are adaptor proteins that negatively regulate Ras–Erk signaling downstream of protein tyrosine kinases (PTKs). Here, we demonstrate that LPS rapidly induced the tyrosine phosphorylation and adaptor function of these proteins. The stimulation with LPS of macrophages from mice lacking Dok-1 or Dok-2 induced elevated Erk activation, but not the other MAP kinases or NF-κB, resulting in hyperproduction of TNF-α and nitric oxide. Furthermore, the mutant mice showed hyperproduction of TNF-α and hypersensitivity to LPS. However, macrophages from these mutant mice reacted normally to other pathogenic molecules, CpG oligodeoxynucleotides, poly(I:C) ribonucleotides, or Pam3CSK4 lipopeptide, which activated cognate TLRs but induced no tyrosine phosphorylation of Dok-1 or Dok-2. Forced expression of either adaptor, but not a mutant having a Tyr/Phe substitution, in macrophages inhibited LPS-induced Erk activation and TNF-α production. Thus, Dok-1 and Dok-2 are essential negative regulators downstream of TLR4, implying a novel PTK-dependent pathway in innate immunity.
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