NOS1-derived nitric oxide promotes NF-κB transcriptional activity through inhibition of suppressor of cytokine signaling-1.
NOS1-derived nitric oxide promotes NF-κB transcriptional activity through inhibition of suppressor of cytokine signaling-1.
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DOI：
10.1084/jem.20140654
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发表时间：
2015-09-21
期刊：
影响因子：
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通讯作者：
Bonini MG
中科院分区：
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作者：
Baig MS;Zaichick SV;Mao M;de Abreu AL;Bakhshi FR;Hart PC;Saqib U;Deng J;Chatterjee S;Block ML;Vogel SM;Malik AB;Consolaro ME;Christman JW;Minshall RD;Gantner BN;Bonini MG
NOS 1 −/−小鼠在实验性脓毒症模型中表现出炎症反应和组织损伤减少。Baig等表明，巨噬细胞中NOS 1衍生的NO产生导致SOCS 1的蛋白水解，以减轻其对TLR 4介导的应答中NFkB转录活性的抑制。NF-κB通路是炎症调节的中心。在这里，我们证明了低输出型一氧化氮（NO）合酶1（NOS 1或nNOS）通过促进NF-κB的活性在炎症反应中起着关键作用。具体来说，巨噬细胞中NOS 1衍生的NO产生导致细胞因子信号传导抑制因子1（SOCS 1）的蛋白质水解，减轻其对NF-κB转录活性的抑制。因此，NOS 1 −/−小鼠在两种不同的脓毒症模型下表现出细胞因子产生减少、肺损伤和死亡率降低。分离的NOS 1 −/−巨噬细胞在用革兰氏阴性细菌LPS激发时表现出类似的促炎性转录缺陷。因此，我们发现，与野生型细胞相比，活化的NOS 1 −/−巨噬细胞含有增加的SOCS 1蛋白和降低的p65蛋白水平。SOCS 1的NOS 1依赖性S-亚硝化损害其与p65的结合，并靶向SOCS 1进行蛋白水解。用外源性NO处理NOS 1 −/−细胞可以拯救SOCS 1降解和p65蛋白的稳定。点突变分析表明，SOCS 1上的Cys 147和Cys 179都是其NO依赖性降解所必需的。这些研究结果表明，NOS 1衍生的NO在调节TLR 4介导的炎症基因转录，以及由此产生的宿主免疫应答的强度和持续时间中起着重要作用。
NOS1−/− mice show reduced inflammatory responses and tissue damage in experimental sepsis models. Baig et al show that NOS1-derived NO production in macrophages leads to proteolysis of SOCS1 to alleviate its repression of NFkB transcriptional activity in response to TLR4-mediated responses. The NF-κB pathway is central to the regulation of inflammation. Here, we demonstrate that the low-output nitric oxide (NO) synthase 1 (NOS1 or nNOS) plays a critical role in the inflammatory response by promoting the activity of NF-κB. Specifically, NOS1-derived NO production in macrophages leads to proteolysis of suppressor of cytokine signaling 1 (SOCS1), alleviating its repression of NF-κB transcriptional activity. As a result, NOS1−/− mice demonstrate reduced cytokine production, lung injury, and mortality when subjected to two different models of sepsis. Isolated NOS1−/− macrophages demonstrate similar defects in proinflammatory transcription on challenge with Gram-negative bacterial LPS. Consistently, we found that activated NOS1−/− macrophages contain increased SOCS1 protein and decreased levels of p65 protein compared with wild-type cells. NOS1-dependent S-nitrosation of SOCS1 impairs its binding to p65 and targets SOCS1 for proteolysis. Treatment of NOS1−/− cells with exogenous NO rescues both SOCS1 degradation and stabilization of p65 protein. Point mutation analysis demonstrated that both Cys147 and Cys179 on SOCS1 are required for its NO-dependent degradation. These findings demonstrate a fundamental role for NOS1-derived NO in regulating TLR4-mediated inflammatory gene transcription, as well as the intensity and duration of the resulting host immune response.