IFN- g Potentiates Atherosclerosis in ApoE Knock-out Mice

The early colocalization of T cells and the potent immunostimulatory cytokine IFNg 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 IFNg in this process. First, the presence of CD4 1 and CD8 1 cells, which secrete lesional IFNg , was documented in apoE 0 atheromata. Then, the apoE 0 mice were crossed with IFNg receptor (IFN g R) 0 mice to generate apoE 0/IFN g R 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 IFNg 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 IFNg signaling may lead to the formation of more lipid-poor and stable atheromata. ( J. Clin. Invest. 1997. 99:2752–2761.)

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