细胞因子信号抑制因子1
NOS1号
细胞因子
促炎细胞因子
细胞生物学
生物
一氧化氮合酶
一氧化氮
TLR4型
肿瘤坏死因子α
炎症
信号转导
NF-κB
免疫学
化学
生物化学
抑制器
内分泌学
基因
作者
Mirza S. Baig,Sofia Zaichick,Mao Mao,André Luelsdorf Pimenta de Abreu,Farnaz R. Bakhshi,Peter C. Hart,Uzma Saqib,Jing Deng,Saurabh Chatterjee,Michelle L. Block,Stephen M. Vogel,Asrar B. Malik,Márcia Edilaine Lopes Consolaro,John W. Christman,Richard D. Minshall,Benjamin N. Gantner,Marcelo G. Bonini
摘要
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.
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