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J. Biol. Chem. 281 (47): 35686-35698

© 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

Nitrated Fatty Acids: Endogenous Anti-inflammatory Signaling Mediators*

Formula

Taixing Cui{ddagger}12, Francisco J. Schopfer§23, Jifeng Zhang{ddagger}, Kai Chen{ddagger}, Tomonaga Ichikawa{ddagger}, Paul R. S. Baker§4, Carlos Batthyany§, Balu K. Chacko3, Xu Feng, Rakesh P. Patel, Anupam Agarwal||, Bruce A. Freeman§5, , and Yuqing E. Chen{ddagger}6

{ddagger}Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan 48109, the §Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, the Department of Pathology and ||Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294

Abstract: Nitroalkene derivatives of linoleic acid (LNO2) and oleic acid (OA-NO2) are present; however, their biological functions remain to be fully defined. Herein, we report that LNO2 and OA-NO2 inhibit lipopolysaccharide-induced secretion of proinflammatory cytokines in macrophages independent of nitric oxide formation, peroxisome proliferator-activated receptor-{gamma} activation, or induction of heme oxygenase-1 expression. The electrophilic nature of fatty acid nitroalkene derivatives resulted in alkylation of recombinant NF-{kappa}B p65 protein in vitro and a similar reaction with p65 in intact macrophages. The nitroalkylation of p65 by fatty acid nitroalkene derivatives inhibited DNA binding activity and repressed NF-{kappa}B-dependent target gene expression. Moreover, nitroalkenes inhibited endothelial tumor necrosis factor-{alpha}-induced vascular cell adhesion molecule 1 expression and monocyte rolling and adhesion. These observations indicate that nitroalkenes such as LNO2 and OA-NO2, derived from reactions of unsaturated fatty acids and oxides of nitrogen, are a class of endogenous anti-inflammatory mediators.


Received for publication April 7, 2006. Revision received July 21, 2006.

* This work was supported by National Institutes of Health Grants HL068878, HL075397, and S06GM08248 (to Y. E. C.), HL70146 (to R. P. P.), and HL58115 and HL64937 (to B. A. F.). 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.


Formula

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1, Fig. 1, and Movie 1.

1 Supported by American Diabetes Association Grant JFA 7-05-JF-12.

2 These authors contributed equally to this work.

3 Supported by the postdoctoral fellowships from the American Heart Association Southeast Affiliate.

4 Supported by National Institutes of Health Cardiovascular Hypertension Training Grant T32HL07457.

5 To whom correspondence may be addressed. Tel.: 412-648-9319; Fax: 412-648-2229; E-mail: freerad{at}pitt.edu. 6 To whom correspondence may be addressed. Tel.: 734-763-7838; Fax: 734-936-2641; E-mail: echenum{at}umich.edu.


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