title: Lipopolysaccharide-induced leukocyte lipid body formation in vivo: innate immunity elicited intracellular Loci involved in eicosanoid metabolism.
abstract: Lipid bodies are rapidly inducible, specialized cytoplasmic domains for eicosanoid-forming enzyme localization, which we hypothesize to have specific roles in enhanced inflammatory mediator production during pathological conditions, including sepsis. However, little is known about the origins, composition, or functions of lipid bodies in vivo. We show that lipid body numbers were increased in leukocytes from septic patients in comparison with healthy subjects. Analogously, the intrathoracic administration of LPS into mice induced a dose- and time-dependent increase in lipid body numbers. Pretreatment with anti-CD14 or anti-CD11b/CD18 mAb drastically inhibited LPS-induced lipid body formation. Moreover, LPS failed to form lipid bodies in C3H/HeJ (TLR4 mutated) mice, demonstrating a requisite role for LPS receptors in lipid body formation. LPS-induced lipid body formation was also inhibited by the platelet-activating factor-receptor antagonists, suggesting a role for endogenous platelet-activating factor. The eicosanoid-forming enzymes, 5-lipoxygenase and cyclooxygenase-2, were immunolocalized within experimentally induced (LPS in mice) or naturally occurring (septic patients) lipid bodies. The proinflammatory cytokine involved in the pathogenesis of sepsis, TNF-alpha, was also shown to colocalize within lipid bodies. Prior stimulation of leukocytes to form lipid bodies enhanced the capacity of leukocytes to produce leukotriene B(4) and PGE(2). In conclusion, our studies indicate that lipid bodies formed after LPS stimulation and sepsis are sites for eicosanoid-forming enzymes and cytokine localization and may develop and function as structurally distinct, intracellular sites for paracrine eicosanoid synthesis during inflammatory conditions.
authors.affiliation: Laboratório de Imunofarmacologia, Departamento de Fisiologia e Farmacodinâmica, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Pacheco
authors.forename: Fernando A
authors.initials: FA
authors.lastname: Bozza
authors.forename: Rachel N
authors.initials: RN
authors.lastname: Gomes
authors.forename: Marcelo
authors.initials: M
authors.lastname: Bozza
authors.forename: Peter F
authors.initials: PF
authors.lastname: Weller
authors.forename: Hugo C
authors.initials: HC
authors.lastname: Castro-Faria-Neto
authors.forename: Patrícia T
authors.initials: PT
authors.lastname: Bozza
mesh_terms: D000328:Adult; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016022:Case-Control Studies; D051546:Cyclooxygenase 2; D015777:Eicosanoids / Q000378:metabolism*; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050356:Lipid Metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008809:Mice, Inbred C3H; D008808:Mice, Inbred CBA; D008875:Middle Aged; D010972:Platelet Activating Factor / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D018805:Sepsis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012772:Shock, Septic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015777:Eicosanoids; D018836:Inflammation Mediators; D007527:Isoenzymes; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases