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NOS1-derived nitric oxide promotes NF-κB transcriptional activity through inhibition of suppressor of cytokine signaling-1. J Exp Med 2015 Sep 21;212(10):1725-38

Date

09/02/2015

Pubmed ID

26324446

Pubmed Central ID

PMC4577833

DOI

10.1084/jem.20140654

Scopus ID

2-s2.0-84961216724   51 Citations

Abstract

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.

Author List

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

Author

Benjamin N. Gantner PhD Assistant Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cytokines
Humans
Lipopolysaccharides
Macrophages
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Molecular Sequence Data
NF-kappa B
Nitric Oxide
Nitric Oxide Synthase Type I
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III
Sepsis
Suppressor of Cytokine Signaling 1 Protein
Suppressor of Cytokine Signaling Proteins
Toll-Like Receptor 4
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a