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J. Biol. Chem., Vol. 279, Issue 46, 48389-48396, November 12, 2004

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A Lipid Peroxidation-derived Inflammatory Mediator

IDENTIFICATION OF 4-HYDROXY-2-NONENAL AS A POTENTIAL INDUCER OF CYCLOOXYGENASE-2 IN MACROPHAGES^*

Takeshi Kumagai, Nao Matsukawa, Yayoi Kaneko, Yoshiaki Kusumi, Masako Mitsumata, and Koji Uchida¶||

From the Graduate School of Bioagricultural Sciences and ^¶Institute for Advanced Research, Nagoya University, Nagoya 464–8601 and the Department of Pathology, Nihon University School of Medicine, Tokyo 173–8610, Japan

Cyclooxygenases (COXs) catalyze the conversion of arachidonic acid to eicosanoids, which mediate a variety of biological actions involved in vascular pathophysiology. In the present study, we investigated the role of lipid peroxidation products in the up-regulation of COX-2, an inducible isoform responsible for high levels of prostaglandin production during inflammation and immune responses. COX-2 was found to colocalize with 4-hydroxy-2-nonenal (HNE), a major lipid peroxidation-derived aldehyde, in foamy macrophages within human atheromatous lesions, suggesting that COX-2 expression may be associated with the accumulation of lipid peroxidation products within macrophages. To test the hypothesis that lipid peroxidation products might be involved in the regulation of prostanoid biosynthesis, we conducted a screen of oxidized fatty acid metabolites and found that, among the compounds tested, only HNE showed inducibility of the COX-2 protein in RAW264.7 macrophages. In addition, intraperitoneal administration of HNE resulted in an increase in cell numbers in the peritoneal cavity that was associated with significant increases in the peritoneal and tissue levels of COX-2 in mice. To understand the possible signaling mechanism underlying the inducing effect of HNE on COX-2 up-regulation, we examined the phosphorylation events that may lead to COX-2 induction and found that HNE did not stimulate the induction of nitric oxide synthase and activation of NF-B but significantly activated p38 mitogen-activated protein kinase and its upstream kinase in RAW264.7 macrophages. Tyrosine kinases, such as the epidermal growth factor-like and Src family tyrosine kinases, appeared to mediate the stabilization of COX-2 mRNA via the p38 mitogen-activated protein kinase pathway. These findings suggest that HNE accumulated in macrophages/foam cells may represent an inflammatory mediator that plays a role in stimulation of the inflammatory response and contributes to the progression of atherogenesis.

Received for publication, August 30, 2004 , and in revised form, September 7, 2004.

^* This work was supported by a research grant from the Ministry of Education, Culture, Sports, Science, and Technology, by the Center of Excellence (COE) Program in the 21st Century in Japan, and by research fellowships from the Japan Society for the Promotion of Science (to T. K.). 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 a supplemental figure.

^|| To whom correspondence should be addressed: Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464–8601, Japan. Tel.: 81-52-789-4127; Fax: 81-52-789-5741; E-mail: uchidak{at}agr.nagoya-u.ac.jp.

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