title: Monocyte chemoattractant protein-1 and 5-lipoxygenase products recruit leukocytes in response to platelet-activating factor-like lipids in oxidized low-density lipoprotein.
abstract: Oxidized low-density lipoprotein (LDL) contains inflammatory agents, including oxidatively fragmented phospholipids that activate the platelet-activating factor (PAF) receptor, but in vivo events caused by these pathologically generated agents are not well defined. Injection of PAF-like lipids derived from oxidized LDL, or C(4)-PAF that is a major PAF-like lipid in these particles, into the pleural cavity of mice resulted in rapid monocyte, neutrophil, and eosinophil accumulation. Increased numbers of intracellular lipid bodies in these cells show they were in an inflammatory environment. Leukocyte recruitment was abolished by a PAF receptor antagonist, as expected. PAF-like lipids induced 5-lipoxygenase expression in leukocytes, mRNA expression for monocyte chemoattractant protein-1 (MCP-1) and other chemokines, synthesis of MCP-1, and leukotriene B(4). The 5-lipoxygenase inhibitor zileuton impaired neutrophil influx, while MCP-1 had a more global role, as determined with MCP-1(-/-) mice. The lack of MCP-1 abrogated leukocyte accumulation and lipid body formation both in vivo and in vitro and chemokine transcription in vivo, and reduced in vivo leukotriene B(4) production. Thus, PAF-like phospholipids in oxidized LDL induce an inflammatory infiltrate through the PAF receptor, chemokine transcription, lipid body formation, and 5-lipoxygenase expression in leukocytes. MCP-1 has a key role in this inflammatory response, and 5-lipoxygenase products are essential for neutrophil recruitment into the inflamed pleural cavity.
authors.affiliation: Departamento de Fisiologia e Farmacodinâmica, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Adriana R
authors.initials: AR
authors.lastname: Silva
authors.forename: Edson F
authors.initials: EF
authors.lastname: de Assis
authors.forename: Lara F C
authors.initials: LF
authors.lastname: Caiado
authors.forename: Gopal K
authors.initials: GK
authors.lastname: Marathe
authors.forename: Marcelo T
authors.initials: MT
authors.lastname: Bozza
authors.forename: Thomas M
authors.initials: TM
authors.lastname: McIntyre
authors.forename: Guy A
authors.initials: GA
authors.lastname: Zimmerman
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Prescott
authors.forename: Patricia T
authors.initials: PT
authors.lastname: Bozza
authors.forename: Hugo C
authors.initials: HC
authors.lastname: Castro-Faria-Neto
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D004224:Diterpenes; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D046934:Ginkgolides; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D007783:Lactones / Q000494:pharmacology; D007962:Leukocytes / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010743:Phospholipids / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D010996:Pleural Effusion / Q000378:metabolism / Q000473:pathology; D010998:Pleurisy / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D018932:Chemokine CCL2; D018925:Chemokines; D004224:Diterpenes; D046934:Ginkgolides; D007783:Lactones; D008077:Lipoproteins, LDL; D010743:Phospholipids; D010972:Platelet Activating Factor; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; C045856:ginkgolide B; D001094:Arachidonate 5-Lipoxygenase