title: Activation of human monocyte-derived macrophages by immune complexes containing low-density lipoprotein.
abstract: Human monocyte-derived macrophages are transformed into foam cells upon incubation with immune complexes containing low-density lipoprotein (LDL-IC), which are internalized predominantly through Fc gamma receptor-mediated phagocytosis. We investigated whether the FcR gamma-mediated ingestion of LDL-IC is associated with functional and metabolic activation of the ingesting cells. As end points we used the assay of released interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) and the reduction of nitroblue tetrazolium, which measures the respiratory burst. LDL-IC, added to the macrophages in concentrations known to induce intracellular accumulation of cholesterol esters and foam cell transformation, stimulated both the cytokine release and the respiratory burst more efficiently than control immune complexes. Time course studies of cytokine release and mRNA expression suggest that the synthesis and release of these two cytokines is under independent control. TNF alpha was released almost immediately after addition of LDL-IC to the macrophages, coinciding with increased early expression of TNF alpha mRNA, detectable 30 min after stimulation. In contrast, IL-1 beta was only increased in stimulated cell supernatants after 8 hr, and the onset of expression of IL-1 beta mRNA was also delayed in comparison to that of TNF alpha mRNA. We noted wide variations in the amounts of TNF alpha released by monocyte-derived macrophages from different donors. We also found that those macrophages which released higher levels of TNF alpha also took up higher amounts of 125I-labeled LDL, suggesting that the expression of LDL receptors by LDL-IC-stimulated macrophages is somehow linked to the degree of activation of these cells. Experiments using the measurement of the oxidative burst as end point corroborated that LDL-IC cause a general activation of macrophage functions. In conclusion, human macrophages are efficiently activated by LDL-IC, as reflected by the release of IL-1 beta and TNF alpha and by the release of oxygen active radicals. Thus, the presentation of LDL-IC to human macrophages induces a variety of metabolic and functional changes which are likely to contribute, directly or indirectly, to endothelial damage and progression of the atheromatous lesion.
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston 29425, USA.
authors.forename: G
authors.initials: G
authors.lastname: Virella
authors.forename: J F
authors.initials: JF
authors.lastname: Muñoz
authors.forename: G M
authors.initials: GM
authors.lastname: Galbraith
authors.forename: C
authors.initials: C
authors.lastname: Gissinger
authors.forename: C
authors.initials: C
authors.lastname: Chassereau
authors.forename: M F
authors.initials: MF
authors.lastname: Lopes-Virella
mesh_terms: D000936:Antigen-Antibody Complex / Q000737:chemistry* / Q000494:pharmacology*; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000032:analysis*; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000737:chemistry / Q000648:ultrastructure; D009000:Monocytes / Q000166:cytology*; D009580:Nitroblue Tetrazolium / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011973:Receptors, LDL / Q000502:physiology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000936:Antigen-Antibody Complex; D007375:Interleukin-1; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; D009580:Nitroblue Tetrazolium