title: IFN-gamma potentiates atherosclerosis in ApoE knock-out mice.
abstract: The early colocalization of T cells and the potent immunostimulatory cytokine IFN-gamma to atherosclerotic lesions suggest that the immune system contributes to atherogenesis. Since mice with a targeted disruption of the apoE gene (apoE 0 mice) develop profound atherosclerosis, we examined the role of IFN-gamma in this process. First, the presence of CD4(+) and CD8(+) cells, which secrete lesional IFN-gamma, was documented in apoE 0 atheromata. Then, the apoE 0 mice were crossed with IFN-gamma receptor (IFNgammaR) 0 mice to generate apoE 0/IFNgammaR 0 mice. Compared to the apoE 0 mice, the compound knock-out mice exhibited a substantial reduction in atherosclerotic lesion size, a 60% reduction in lesion lipid accumulation, a decrease in lesion cellularity, but a marked increase in lesion collagen content. Evaluation of the plasma lipoproteins showed that the compound knockout mice had a marked increase in potentially atheroprotective phospholipid/apoA-IV rich particles as well. This correlated with an induction of hepatic apoA-IV transcripts. These observations suggest that IFN-gamma promotes and modifies atherosclerosis through both local effects in the arterial wall as well as a systemic effect on plasma lipoproteins. Therefore, therapeutic inhibition of IFN-gamma signaling may lead to the formation of more lipid-poor and stable atheromata.
authors.affiliation: Department of Medicine, Columbia University, New York 10032, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gupta
authors.forename: A M
authors.initials: AM
authors.lastname: Pablo
authors.forename: X c
authors.initials: Xc
authors.lastname: Jiang
authors.forename: N
authors.initials: N
authors.lastname: Wang
authors.forename: A R
authors.initials: AR
authors.lastname: Tall
authors.forename: C
authors.initials: C
authors.lastname: Schindler
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology; D000096743:Interferon gamma Receptor
chemical_list: D001057:Apolipoproteins E; D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor