Abstract 641: Interleukin-15 Plays a Role in Atherosclerosis Through Effects on Multiple Inflammatory Cells in ApoE-/- Mice

Objective: Interleukin (IL)-15 is a pro-inflammatory cytokine which is essential for the survival and maturation of natural killer (NK) and CD8+ T cells and has recently been reported to directly activate macrophages. In the present study, we used IL-15 overexpressing and IL-15 knockout mice to determine its effect on atherosclerosis in apolipoprotein E knockout (apoE-/-) mice. Approach and Results: Deficiency of IL-15 reduced atherosclerosis while overexpression of IL-15 increased atherosclerosis despite opposite effects on plasma lipoprotein cholesterol levels. Genetic ablation of IL-15 in apoE-/- mice resulted in a lack of NK cells and reduced populations of monocytes and CD8+ T cells, whereas overexpression of IL-15 had the opposite effects. CD8+ T cells were detected in atherosclerotic plaques from apoE-/- mice, were increased in plaques from il-15TgapoE-/- mice and were virtually absent from plaques from il15-/- apoE-/- mice. To test the role of NK, NKT and activated CD8+ T cells in atherosclerosis, NK1.1+ cells were immuno-depleted from apoE-/- mice. Atherosclerosis was reduced but to a lesser extent than in age matched il15-/- apoE-/- mice. Plaques from these mice, however, were almost devoid of CD8+ T cells. ApoE-/- mice that were heterozygous for IL-15 (il15+/-apoE-/-) exhibited normal levels of NK, NKT, CD8T cells and monocytes however atherosclerosis was reduced by 40-50 % compared to control apoE-/- mice. This suggested that IL-15 also affects atherosclerosis through NK/NKT and CD8+ T cell independent pathways. Treatment of macrophages with recombinant IL-15 in vitro induced inflammatory cytokines and foam cell formation. Furthermore, reduced levels of MCP-1 and CD11b immune-reactivity were detected in plaques from il15-/- apoE-/- compared to control apoE-/- mice. Conclusions: IL-15 plays a significant role in promoting atherosclerosis through pathways affecting multiple inflammatory cells including the survival/recruitment of NK, NKT and CD8+ T cells, the modulation of monocyte levels, and direct activation of macrophages.