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J. Biol. Chem., Vol. 283, Issue 29, 19927-19935, July 18, 2008

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Electrophilic Cyclopentenone Neuroprostanes Are Anti-inflammatory Mediators Formed from the Peroxidation of the -3 Polyunsaturated Fatty Acid Docosahexaenoic Acid^*

Erik S. Musiek, Joshua D. Brooks, Myungsoo Joo, Enrico Brunoldi, Alessio Porta, Giuseppe Zanoni, Giovanni Vidari, Timothy S. Blackwell^¶, Thomas J. Montine^||, Ginger L. Milne, BethAnn McLaughlin^**, and Jason D. Morrow¹

From the Division of Clinical Pharmacology, ^¶Division of Pulmonary and Critical Care Medicine, and ^**Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, the Department of Organic Chemistry, University of Pavia, Pavia 27100, Italy, and the ^||Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98104

The -3 polyunsaturated fatty acid docosahexaenoic acid (DHA) possesses potent anti-inflammatory properties and has shown therapeutic benefit in numerous inflammatory diseases. However, the molecular mechanisms of these anti-inflammatory properties are poorly understood. DHA is highly susceptible to peroxidation, which yields an array of potentially bioactive lipid species. One class of compounds are cyclopentenone neuroprostanes (A₄/J₄-NPs), which are highly reactive and similar in structure to anti-inflammatory cyclopentenone prostaglandins. Here we show that a synthetic A₄/J₄-NP, 14-A₄-NP (A₄-NP), potently suppresses lipopolysaccharideinduced expression of inducible nitric-oxide synthase and cyclooxygenase-2 in macrophages. Furthermore, A₄-NP blocks lipopolysaccharide-induced NF-B activation via inhibition of I kinase-mediated phosphorylation of IB. Mutation on I kinase β cysteine 179 markedly diminishes the effect of A₄-NP, suggesting that A₄-NP acts via thiol modification at this residue. Accordingly, the effects of A₄-NP are independent of peroxisome proliferator-activated receptor- and are dependent on an intact reactive cyclopentenone ring. Interestingly, free radical-mediated oxidation of DHA greatly enhances its anti-inflammatory potency, an effect that closely parallels the formation of A₄/J₄-NPs. Furthermore, chemical reduction or conjugation to glutathione, both of which eliminate the bioactivity of A₄-NP, also abrogate the anti-inflammatory effects of oxidized DHA. Thus, we have demonstrated that A₄/J₄-NPs, formed via the oxidation of DHA, are potent inhibitors of NF-B signaling and may contribute to the anti-inflammatory actions of DHA. These findings have implications for understanding the anti-inflammatory properties of -3 fatty acids, and elucidate novel interactions between lipid peroxidation products and inflammation.

Received for publication, May 12, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grants GM15431, CA77839, DK48831, and ES13125. This work was also supported by the Italian MIUR and Regione Lombardia, Direzione Generale Sanità. 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 Clinical Pharmacology, Vanderbilt University Medical Center, 536 RRB, 2222 Pierce Ave., 37232. Fax: 615-322-3669; E-mail: jason.morrow{at}vanderbilt.edu.

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