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

Mirza Saqib Baig, Sofia V. Zaichick, Mao Mao, Andre L. de Abreu, Farnaz R. Bakhshi, Peter C. Hart, Uzma Saqib, Jing Deng, Saurabh Chatterjee, Michelle L. Block, Stephen M. Vogel, Asrar B. Malik, Marcia E.L. Consolaro, John W. Christman, Richard D. Minshall, Benjamin N. Gantner, Marcelo G. Bonini

Research output: Contribution to journalArticle

48 Scopus 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.

Original languageEnglish (US)
Pages (from-to)1725-1738
Number of pages14
JournalJournal of Experimental Medicine
Volume212
Issue number10
DOIs
StatePublished - Sep 21 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Baig, M. S., Zaichick, S. V., Mao, M., de Abreu, A. L., Bakhshi, F. R., Hart, P. C., Saqib, U., Deng, J., Chatterjee, S., Block, M. L., Vogel, S. M., Malik, A. B., Consolaro, M. E. L., Christman, J. W., Minshall, R. D., Gantner, B. N., & Bonini, M. G. (2015). NOS1-derived nitric oxide promotes NF-κB transcriptional activity through inhibition of suppressor of cytokine signaling-1. Journal of Experimental Medicine, 212(10), 1725-1738. https://doi.org/10.1084/jem.20140654