G. Virella et al., ACTIVATION OF HUMAN MONOCYTE-DERIVED MACROPHAGES BY IMMUNE-COMPLEXES CONTAINING LOW-DENSITY-LIPOPROTEIN, Clinical immunology and immunopathology, 75(2), 1995, pp. 179-189
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.