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The Journal of Immunology, 2003, 171: 2090-2098.
Copyright © 2003 by The American Association of Immunologists

Synergism Between Platelet-Activating Factor-Like Phospholipids and Peroxisome Proliferator-Activated Receptor {gamma} Agonists Generated During Low Density Lipoprotein Oxidation That Induces Lipid Body Formation in Leukocytes1

Edson F. de Assis*, Adriana R. Silva*, Lara F. C. Caiado*, Gopal K. Marathe{dagger}, Guy A. Zimmerman{ddagger},§, Stephen M. Prescott{ddagger},¶, Thomas M. McIntyre{dagger},{ddagger},§, Patricia T. Bozza* and Hugo C. de Castro-Faria-Neto2,*

* Laboratório de Imunofarmacologia, Departamento de Fisiologia e Farmacodinâmica, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil; and Departments of {dagger} Pathology and {ddagger} Internal Medicine, § Program in Human Molecular Biology and Genetics, and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112

Oxidized low density lipoprotein (LDL) has an important proinflammatory role in atherogenesis. In this study, we investigated the ability of oxidized LDL (oxLDL) and its phospholipid components to induce lipid body formation in leukocytes. Incubation of mouse peritoneal macrophages with oxidized, but not with native LDL led to lipid body formation within 1 h. This was blocked by platelet-activating factor (PAF) receptor antagonists or by preincubation of oxLDL with rPAF acetylhydrolase. HPLC fractions of phospholipids purified from oxLDL induced calcium flux in neutrophils as well as lipid body formation in macrophages. Injection of the bioactive phospholipid fractions or butanoyl and butenoyl PAF, a phospholipid previously shown to be present in oxLDL, into the pleural cavity of mice induced lipid body formation in leukocytes recovered after 3 h. The 5-lipoxygenase and cyclooxygenase-2 colocalized within lipid bodies formed after stimulation with oxLDL, bioactive phospholipid fractions, or butanoyl and butenoyl PAF. Lipid body formation was inhibited by 5-lipoxygenase antagonists, but not by cyclooxygenase-2 inhibitors. Azelaoyl-phosphatidylcholine, a peroxisome proliferator-activated receptor-{gamma} agonist in oxLDL phospholipid fractions, induced formation of lipid bodies at late time points (6 h) and synergized with suboptimal concentrations of oxLDL. We conclude that lipid body formation is an important proinflammatory effect of oxLDL and that PAF-like phospholipids and peroxisome proliferator-activated receptor-{gamma} agonists generated during LDL oxidation are important mediators in this phenomenon.




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