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J. Biol. Chem., Vol. 282, Issue 42, 30667-30672, October 19, 2007

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NOS2 Regulation of NF-B by S-Nitrosylation of p65^*

From the Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University, Medical Center, Durham, North Carolina 27710

Signal transduction in the NF-B transcription factor pathway is inhibited by inducible nitric oxide synthase (NOS2) activity, although the molecular mechanism(s) are incompletely understood. We have previously shown that nitric oxide (NO), derived from NOS2 consequent upon cytokine stimulation, attenuates NF-B p50-p65 heterodimer DNA binding and have identified the p50 monomer as a locus for inhibitory S-nitrosylation. We now show that the binding partner of p50, NF-B p65, is also targeted by NO following cytokine stimulation of respiratory epithelial cells and macrophages and identify a conserved cysteine within the Rel homology domain that is the site for S-nitrosylation. S-Nitrosylation of p65 inhibits NF-B-dependent gene transcription, and nuclear levels of S-nitrosylated p65 correlate with decreased DNA binding of the p50-p65 heterodimer. NOS2 regulates cytokine-induced S-nitrosylation of p65, resulting in decreased NF-B binding to the NOS2 promoter, thereby inhibiting further NOS2 expression. Collectively, these findings delineate a mechanism by which NOS2 modulates NF-B activity and regulates gene expression in inflammation.

Received for publication, July 19, 2007 , and in revised form, August 24, 2007.

^* This work was supported by National Institutes of Health Grant K08HL004287 (to H. E. M.) and U19 ES012496 (to J. S. S.) and a grant from the American Lung Association (to H. E. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, Box 2613, MSRB 201, Durham, NC 27710. Tel.: 919-668-0381; Fax: 919-668-0494; E-mail: marsh015{at}mc.duke.edu.

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