Induction of monocyte differentiation and foam cell formation in vitro by 7-ketocholesterol

Oxidized LDL (OxLDL) is composed of many potentially proatherogenic molecules, including oxysterols. Of the oxysterols, 7-ketocholesterol (7-KC) is found in rela- tively large abundance in OxLDL, as well as in atheroscle- rotic plaque and foam cells in vivo. Although there is evi- dence that 7-KC activates endothelial cells, its effect on monocytes is unknown. We tested the hypothesis that 7-KC may induce monocyte differentiation and promote foam cell formation. THP-1 cells were used as a monocyte model system and were treated with 7-KC over a range of concen- trations from 0.5 to 10 m g/ml. Changes in cell adhesion properties, cell morphology, and expression of antigens characteristic of differentiated macrophages were moni- tored over a 7-day period. 7-KC promoted cells to firmly ad- here and display morphologic features of differentiated macrophages; this effect was time and dose dependent and was markedly more potent than cholesterol treatment (45% of cells became adherent after 7 days of treatment with 7-KC at 10 m g/ml vs. less then 5% for control cells, P , 0.01). Similar effects were obtained when LDL enriched with 7-KC or OxLDL were added to THP-1 cells. 7-KC- differentiated cells expressed CD11b, CD36, and CD68, phagocytized latex beads, and formed lipid-laden foam cells after exposure to acetylated LDL or OxLDL. In con- trast to 7-KC, oxysterols with known cell regulatory effects such as 25-hydroxycholesterol, 7 b -hydroxycholesterol, and (22 R )-hydroxycholesterol did not effectively promote THP-1 differentiation. In conclusion, these results demonstrate for the first time that 7-KC, a prominent oxysterol formed in OxLDL by peroxidation of cholesterol, may play an im- portant role in promoting monocyte differentiation and foam cell formation. These studies also suggest that 7-KC in- duces monocyte differentiation through a sterol-mediated reg- ulatory pathway that remains to be characterized. —Hayden, J. M., L. Brachova, K. Higgins, L. Obermiller, A. Sevanian, S. Khandrika, and P. D. Reaven. Induction of monocyte differen- tiation and foam cell formation in vitro by 7-ketocholesterol. J. Lipid Res. 2002. 43: 26-35.