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 leukocytes.
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.
de Assis
Edson F
EF
Laboratório de Imunofarmacologia, Departamento de Fisiologia e Farmacodinâmica, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
Silva
Adriana R
AR
Caiado
Lara F C
LF
Marathe
Gopal K
GK
Zimmerman
Guy A
GA
Prescott
Stephen M
SM
McIntyre
Thomas M
TM
Bozza
Patricia T
PT
de Castro-Faria-Neto
Hugo C
HC
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism / Q000502:physiology; D051546:Cyclooxygenase 2; D004357:Drug Synergism; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism* / Q000502:physiology; D008077:Lipoproteins, LDL / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D010084:Oxidation-Reduction; D020675:Peroxisomes / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D010743:Phospholipids / Q000378:metabolism; D010972:Platelet Activating Factor / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*; D035422:Pleural Cavity / Q000166:cytology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism / Q000502:physiology*; D035423:Thoracic Cavity; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism / Q000502:physiology*
D007527:Isoenzymes; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D010743:Phospholipids; D010972:Platelet Activating Factor; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C099252:oxidized low density lipoprotein; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases