Objective: To examine the role of the balance between interleukin (IL)-1 and IL-1 receptor antagonist (IL-1Ra) in atherosclerosis and vascular inflammation.
Methods: Transgenic (Tg) mice overexpressing either secreted IL-1Ra or intracellular IL-1Ra1 as well as IL-1Ra-deficient mice (IL-1Ra -/-) were crossed with apolipoprotein E-deficient mice (ApoE -/-).
Results: In males fed a cholesterol-rich diet for 10 weeks, average atherosclerotic lesion area within aortic roots was significantly decreased in ApoE -/- secreted IL-1Ra Tg (-47%) and ApoE -/- intracellular IL-1Ra1 Tg (-40%) mice as compared to ApoE -/- non-Tg controls. The extent of sudanophilic lesions was reduced within the thoraco-abdominal aorta in ApoE -/- secreted IL-1Ra (-53%) and ApoE -/- intracellular IL-1Ra1 (-67%) Tg mice. In parallel experiments, we observed early mortality and illness among double deficient mice, whereas ApoE -/- IL-1Ra +/+ and ApoE +/+ IL-1Ra -/- mice were apparently healthy. After 7 weeks of diet, ApoE -/- IL-1Ra -/- mice exhibited massive aortic inflammation with destruction of the vascular architecture, but no signs of atherosclerosis. ApoE -/- IL-1Ra +/+ had atherosclerosis and a moderate inflammatory reaction, whereas ApoE +/+ IL-1Ra -/- mice were free of vascular lesions. Macrophages were present in large amounts within inflammatory lesions in the adventitia of ApoE -/- IL-1Ra -/- mice.
Conclusion: Our results demonstrate that the IL-1/IL-1Ra ratio plays a critical role in the pathogenic mechanisms leading to vascular inflammation and atherosclerosis in ApoE -/- mice.