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J. Biol. Chem., Vol. 282, Issue 50, 36199-36205, December 14, 2007

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Regulation of Peroxiredoxins by Nitric Oxide in Immunostimulated Macrophages^*

Alexandre Diet¹, Kahina Abbas¹, Cécile Bouton, Blanche Guillon, Flora Tomasello, Simon Fourquet, Michel B. Toledano, and Jean-Claude Drapier²

From the Institut de Chimie des Substances Naturelles CNRS, and Laboratoire Stress Oxydants et Cancer, Institut de Biologie et de Technologies de Saclay, Commissariat à l'Energie Atomique-Saclay, 91190 Gif-sur-Yvette, France

Reactive oxygen species and nitric oxide (NO) are capable of both mediating redox-sensitive signal transduction and eliciting cell injury. The interplay between these messengers is quite complex, and intersection of their signaling pathways as well as regulation of their fluxes requires tight control. In this regard, peroxiredoxins (Prxs), a recently identified family of six thiol peroxidases, are central because they reduce H₂O₂, organic peroxides, and peroxynitrite. Here we provide evidence that endogenously produced NO participates in protection of murine primary macrophages against oxidative and nitrosative stress by inducing Prx I and VI expression at mRNA and protein levels. We also show that NO prevented the sulfinylation-dependent inactivation of 2-Cys Prxs, a reversible overoxidation that controls H₂O₂ signaling. In addition, studies using macrophages from sulfiredoxin (Srx)-deficient mice indicated that regeneration of 2-Cys Prxs to the active form was dependent on Srx. Last, we show that NO increased Srx expression and hastened Srx-dependent recovery of 2-Cys Prxs. We therefore propose that modulation by NO of Prx expression and redox state, as well as up-regulation of Srx expression, constitutes a novel pathway that contributes to antioxidant response and control of H₂O₂-mediated signal transduction in mammals.

Received for publication, August 3, 2007 , and in revised form, September 27, 2007.

^* This work was supported by grants from the Agence Nationale de la Recherche (to J.-C. D. and M. B. T.) and from Association pour la Recherche sur le Cancer (to M. B. T.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4 and Table S1.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: ICSN-CNRS, Bât. 27, Ave. de la Terrasse, 91190 Gif-sur-Yvette, France. Fax: 33-1-69-07-72-47; E-mail: drapier{at}icsn.cnrs-gif.fr.

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