NOS1-derived nitric oxide promotes NF-κB transcriptional activity through inhibition of suppressor of cytokine signaling-1

被引:99
作者
Baig, Mirza Saqib [1 ,2 ]
Zaichick, Sofia V. [1 ,2 ]
Mao, Mao [1 ,2 ]
de Abreu, Andre L. [1 ,2 ]
Bakhshi, Farnaz R. [2 ]
Hart, Peter C. [1 ,6 ]
Saqib, Uzma [2 ]
Deng, Jing [1 ]
Chatterjee, Saurabh [3 ]
Block, Michelle L. [4 ]
Vogel, Stephen M. [2 ]
Malik, Asrar B. [2 ]
Consolaro, Marcia E. L. [7 ]
Christman, John W. [1 ]
Minshall, Richard D. [2 ,5 ]
Gantner, Benjamin N. [2 ]
Bonini, Marcelo G. [1 ,2 ,6 ]
机构
[1] Univ Illinois, Coll Med, Dept Med, Chicago, IL 60607 USA
[2] Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60607 USA
[3] Univ Illinois, Coll Med, Dept Anesthesiol, Chicago, IL 60607 USA
[4] Univ Illinois, Coll Med, Dept Pathol, Chicago, IL 60607 USA
[5] Univ S Carolina, Dept Environm Hlth Sci, Columbia, SC 29208 USA
[6] Indiana Univ, Stark Neurosci Res Inst, Dept Anat & Cell Biol, Indianapolis, IN 46202 USA
[7] Univ Estadual Maringa, Programa Biociencias Aplicadas Farm PBF, BR-87020900 Maringa, Parana, Brazil
关键词
SYNTHASE-DEFICIENT MICE; S-NITROSYLATION; MOLECULAR-MECHANISMS; INFLAMMATION; EXPRESSION; P65; ACTIVATION; PROTEIN; MOUSE; SOCS;
D O I
10.1084/jem.20140654
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The NF-kappa B 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-kappa B. Specifically, NOS1-derived NO production in macrophages leads to proteolysis of suppressor of cytokine signaling 1 (SOCS1), alleviating its repression of NF-kappa B 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.
引用
收藏
页码:1725 / 1738
页数:14
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