ACTIVATION OF HUMAN MONOCYTE-DERIVED MACROPHAGES BY IMMUNE-COMPLEXES CONTAINING LOW-DENSITY-LIPOPROTEIN

Human monocyte-derived macrophages are transformed into foam cells upo n incubation with immune complexes containing low-density lipoprotein (LDL-IC), which are internalized predominantly through Fc gamma recept or-mediated phagocytosis. We investigated whether the FcR gamma-mediat ed ingestion of LDL-IC is associated with functional and metabolic act ivation of the ingesting cells. As end points we used the assay of rel eased 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 concentrati ons known to induce intracellular accumulation of cholesterol esters a nd 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 th at the synthesis and release of these two cytokines is under independe nt control. TNF alpha was released almost immediately after addition o f LDL-IC to the macrophages, coinciding with increased early expressio n 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 dif ferent donors. We also found that those macrophages which released hig her levels of TNF alpha also took up higher amounts of I-125-labeled L DL, suggesting that the expression of LDL receptors by LDL-IC-stimulat ed 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 macropha ge functions. In conclusion, human macrophages are efficiently activat ed by LDL-IC, as reflected by the release of IL-1 beta and TNF alpha a nd by the release of oxygen active radicals. Thus, the presentation of LDL-IC to human macrophages induces a variety of metabolic and functi onal changes which are likely to contribute, directly or indirectly, t o endothelial damage and progression of the atheromatous lesion. (C) 1 995 Academic Press, Inc.