IFN-gamma potentiates atherosclerosis in ApoE knock-out mice

J Clin Invest. 1997 Jun 1;99(11):2752-61. doi: 10.1172/JCI119465.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apolipoproteins E / deficiency*
  • Apolipoproteins E / genetics
  • Arteriosclerosis / genetics
  • Arteriosclerosis / immunology*
  • Arteriosclerosis / metabolism
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Interferon-gamma / immunology*
  • Mice
  • Mice, Knockout
  • Receptors, Interferon / genetics
  • Receptors, Interferon / immunology

Substances

  • Apolipoproteins E
  • Receptors, Interferon
  • interferon gamma receptor
  • Interferon-gamma