title: Induction of monocyte differentiation and foam cell formation in vitro by 7-ketocholesterol.
abstract: Oxidized LDL (OxLDL) is composed of many potentially proatherogenic molecules, including oxysterols. Of the oxysterols, 7-ketocholesterol (7-KC) is found in relatively large abundance in OxLDL, as well as in atherosclerotic plaque and foam cells in vivo. Although there is evidence 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 concentrations from 0.5 to 10 microg/ml. Changes in cell adhesion properties, cell morphology, and expression of antigens characteristic of differentiated macrophages were monitored over a 7-day period. 7-KC promoted cells to firmly adhere 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 microg/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 contrast to 7-KC, oxysterols with known cell regulatory effects such as 25-hydroxycholesterol, 7beta-hydroxycholesterol, and (22R)-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 important role in promoting monocyte differentiation and foam cell formation. These studies also suggest that 7-KC induces monocyte differentiation through a sterol-mediated regulatory pathway that remains to be characterized.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine (CS/111E), Carl T. Hayden Veterans Affairs Medical Center, 650 E. Indian School Road, Phoenix, AZ 85012-1892, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Hayden
authors.forename: Libuse
authors.initials: L
authors.lastname: Brachova
authors.forename: Karen
authors.initials: K
authors.lastname: Higgins
authors.forename: Lewis
authors.initials: L
authors.lastname: Obermiller
authors.forename: Alex
authors.initials: A
authors.lastname: Sevanian
authors.forename: Srikrishna
authors.initials: S
authors.lastname: Khandrika
authors.forename: Peter D
authors.initials: PD
authors.lastname: Reaven
mesh_terms: D018955:CD36 Antigens; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005487:Foam Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D007653:Ketocholesterols / Q000378:metabolism / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D008565:Membrane Proteins; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D011971:Receptors, Immunologic / Q000096:biosynthesis; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B
chemical_list: D018955:CD36 Antigens; D006888:Hydroxycholesterols; D007653:Ketocholesterols; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C099252:oxidized low density lipoprotein; C007997:25-hydroxycholesterol; C003001:7-ketocholesterol