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Modulation of Lipid and Protein Mediators of Inflammation by Cytosolic Phospholipase A₂ during Experimental Sepsis¹

Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, Tokyo, Japan

Cytosolic phospholipase A₂ (cPLA₂) is one of the key enzymes in lipid mediator generation. It preferentially hydrolyzes arachidonoyl-phospholipid in response to cellular stimuli, liberating arachidonic acid, the shared precursor of PGs and leukotrienes. Mice with disruption of the cPLA₂ gene exhibit a more than 80% decrease in the generation of these lipid mediators, leading to dramatic phenotypes in various models of inflammatory and allergic disease. In this study, we use the cecal ligation and puncture model of sepsis along with multiplex quantitation systems to explore interactions between eicosanoids and protein mediators. cPLA₂-deficient mice exhibited significantly less weight loss accompanied by decreased generation of PGs, leukotriene B₄, IL-6, and CCL2. Despite these differences, genetic ablation of cPLA₂ did not provide any survival advantage. Unexpectedly, abundant production of 12-hydroxy-eicosatetraenoic acid, another arachidonic acid-derived lipid mediator, was found to be unaffected by disruption of the cPLA₂ gene. Eicosanoid production preceded the production of cytokines. Eicosanoid modulation of IL-6 and CCL2 expression was suggested by scattergram analyses. These results provide in vivo evidence for the rapid generation of eicosanoids, regulatory role(s) for cPLA₂-derived lipid mediators on protein mediator production, and the existence of a robust cPLA₂-independent pathway(s) of eicosanoid generation.

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 This work was supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to T.S. and N.U.), and a grant from Ono Medical Research Foundation (to N.U.).

² Current address: Division of Molecular Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229.

³ Address correspondence and reprint requests to Dr. Takao Shimizu, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail address: tshimizu{at}m.u-tokyo.ac.jp

⁴ Abbreviations used in this paper: CLP, cecal ligation and puncture; COX, cyclooxygenase; cPGI₂, carbaprostacyclin; cPLA₂, cytosolic phospholipase A₂; HETE, hydroxy-eicosatetraenoic acid; LC-MS/MS, liquid chromatography-tandem mass spectrometry; LO, lipoxygenase; LT, leukotriene; PGI₂, prostacyclin; PLA₂, phospholipase A₂; sPLA₂, secretory PLA₂; D(–)-PBS, Dulbecco’s PBS without calcium chloride and magnesium chloride; PAF, platelet-activating factor; Tx, thromboxane.