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J. Biol. Chem., Vol. 278, Issue 46, 45117-45127, November 14, 2003

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Phosphatidic Acid Regulates Systemic Inflammatory Responses by Modulating the Akt-Mammalian Target of Rapamycin-p70 S6 Kinase 1 Pathway^*

Hyung-Kyu Lim, Young-Ae Choi, Wan Park, Taehoon Lee¶, Sung Ho Ryu¶, Seong-Yong Kim, Jae-Ryong Kim, Jung-Hye Kim, and Suk-Hwan Baek||

From the Department of Biochemistry & Molecular Biology, College of Medicine, Yeungnam University, Daegu 705-717, the Department of Microbiology, College of Natural Sciences, Kyungpook National University, Daegu 702-701, and the ^¶Division of Molecular & Life Sciences, Pohang University of Sciences and Technology, Pohang 790-784, South Korea

Macrophages are pivotal effector cells in the innate immune system. When microbial products bind to pathogen recognition receptors, macrophages are activated and release a broad array of mediators, such as cytokines, that orchestrate the inflammatory responses of the host. Phosphatidic acid (PA) has been implicated as an important metabolite of phospholipid biosynthesis and in membrane remodeling and has been further suggested to be a crucial second messenger in various cellular signaling events. Here we show that PA is an essential regulator of inflammatory response. Deleterious effects of PA are associated with the secretion of proinflammatory cytokines, such as tumor necrosis factor-, interleukin-1, interleukin-6, and the production of nitric oxide, prostaglandin E₂, which are predominantly released by macrophage Raw264.7 cells. Furthermore, the administration of PA to mice increased the serum cytokine level. Moreover, direct or lipopolysaccharide-induced PA accumulation by macrophages led to the Akt-dependent activation of the mammalian target of rapamycin-p70 S6 kinase 1, a process required for the induction of inflammatory mediators. These findings demonstrate the importance of the role of PA in systemic inflammatory responses, and provide a potential usefulness as specific targets for the development of therapies.

Received for publication, April 11, 2003 , and in revised form, July 31, 2003.

^* This work was supported by Grant 02-PJ1-PG3-20905-0005 from the Ministry of Health and Welfare, Republic of Korea. 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.

^|| To whom correspondence should be addressed: Dept. of Biochemistry & Molecular Biology, College of Medicine, Yeungnam University, 317-1 Daemyung 5-Dong, Nam-Gu, Daegu 705-717, South Korea. Tel.: 82-53-620-3981; Fax: 82-53-623-8032; E-mail: sbaek{at}med.yu.ac.kr.

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