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 2-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.
Wang
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Division of Molecular Medicine, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Tabas
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Winchester
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R
Ravalli
S
S
Rabbani
L E
LE
Tall
A
A
D001161:Arteriosclerosis / Q000378:metabolism*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism*; D005487:Foam Cells / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D017403:In Situ Hybridization; D016209:Interleukin-8 / Q000096:biosynthesis*; D008264:Macrophages / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D013997:Time Factors
D018932:Chemokine CCL2; D016209:Interleukin-8; D012333:RNA, Messenger; D002784:Cholesterol