Interleukin 8 is induced by cholesterol loading of macrophages and expressed by macrophage foam cells in human atheroma

in order to identify novel genes expressed in macrophage-derived foam cells, we used a multigene assay to examine the expression of genes in control versus cholesterol-loaded macrophages. We compared THP-1 macrophages incubated with or without acetylated LDL (acLDL) +/- acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor (compound 58035) for 20 h and assessed changes in mRNA of chemokines, growth factors, interleukins, and adhesion molecules, Among 49 genes examined, an increase in mRNA was observed only for interleukin 8 (IL-8) in THP-1 macrophages. Northern analysis confirmed a 3 to 4-fold increase of IL-8 mRNA and an enzyme-linked immunosorbent assay (ELISA) revealed a corresponding increase in IL-8 in conditioned medium, Oxidized LDL (oxLDL) also induced IL.8 mRNA but native LDL had no effect, 58035 had a moderate effect on IL-8 induction by acLDL, AcLDL-induced IL-8 expression was concentration- and time-dependent, The time course of IL-8 induction paralleled that of cholesterol loading, MCP-1, a chemokine implicated in recruiting monocytes in atherogenesis, was also induced by acLDL, The induction of MCP-1, however, peaked at 1 h after addition of acLDL and returned to basal level by 20 h while IL-8 induction peaked at 8 h and was still a-fold higher than basal level at 20 h, IL-8 induction was also observed in fresh human monocyte-derived macrophage cells treated with acLDL, Finally, immunohistochemistry and in situ hybridization studies using specimens of human coronary atheromas showed expression of IL-8 mRNA in a macrophage-rich area, We conclude that IL-8 is induced in macrophage foam cells as a response to cholesterol loading, The chemoattractant and/or mitogenic effects of IL-8 on neutrophils, T cells, smooth muscle, or vascular endothelial cells may contribute to the progression and complications of atherosclerosis.