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J. Biol. Chem., Vol. 280, Issue 42, 35562-35570, October 21, 2005

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Cyclopentenone Isoprostanes Inhibit the Inflammatory Response in Macrophages^*

Erik S. Musiek, Ling Gao, Ginger L. Milne, Wei Han¶, M. Brett Everhart¶, Dingzhi Wang, Michael G. Backlund, Raymond N. DuBois¶, Giuseppe Zanoni||, Giovanni Vidari||, Timothy S. Blackwell¶, and Jason D. Morrow¶1

From the Departments of Pharmacology, Cell and Developmental Biology, and ^¶Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 and the ^||Department of Organic Chemistry, University of Pavia, Viale Taramelli, 10-27100 Pavia, Italy

Although both inflammation and oxidative stress contribute to the pathogenesis of many disease states, the interaction between the two is poorly understood. Cyclopentenone isoprostanes (IsoPs), highly reactive structural isomers of the bioactive cyclopentenone prostaglandins PGA₂ and PGJ₂, are formed non-enzymatically as products of oxidative stress in vivo. We have, for the first time, examined the effects of synthetic 15-A₂- and 15-J₂-IsoPs, two groups of endogenous cyclopentenone IsoPs, on the inflammatory response in RAW264.7 and primary murine macrophages. Cyclopentenone IsoPs potently inhibited lipopolysaccharide-stimulated IB degradation and subsequent NF-B nuclear translocation and transcriptional activity. Expression of inducible nitric-oxide synthase and cyclooxygenase-2 were also inhibited by cyclopentenone IsoPs as was nitrite and prostaglandin production (IC₅₀ 360 and 210 nM, respectively). 15-J₂-IsoPs potently activated peroxisome proliferator-activated receptor (PPAR) nuclear receptors, whereas 15-A₂-IsoP did not, although the anti-inflammatory effects of both molecules were PPAR-independent. Interestingly 15-A₂-IsoPs induced oxidative stress in RAW cells that was blocked by the antioxidant 4-hydroxy-TEMPO (TEMPOL) or the mitochondrial uncoupler carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone. TEMPOL also abrogated the inhibitory effect of 15-A₂-IsoPs on lipopolysaccharide-induced NF-B activation, inducible nitricoxide synthase expression, and nitrite production, suggesting that 15-A₂-IsoPs inhibit the NF-B pathway at least partially via a redox-dependent mechanism. 15-J₂-IsoP, but not 15-A₂-IsoP, also potently induced RAW cell apoptosis again via a PPAR -independent mechanism. These findings suggest that cyclopentenone IsoPs may serve as negative feedback regulators of inflammation and have important implications for defining the role of oxidative stress in the inflammatory response.

Received for publication, May 2, 2005 , and in revised form, July 27, 2005.

^* This work was supported by National Institutes of Health Grants GM15431 and DK48831 and a medical student research grant from the Pharmaceutical Research and Manufacturers of America (PhRMA) Foundation (to E. S. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data.

¹ To whom correspondence should be addressed: Division of Clinical Pharmacology, Depts. of Medicine and Pharmacology, Vanderbilt University School of Medicine, 526 RRB, 23rd and Pierce Aves., Nashville, TN 37232-6602. E-mail: jason.morrow{at}vanderbilt.edu.

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