Copyright © 2005, European Society of Cardiology
Interleukin-1 plays a major role in vascular inflammation and atherosclerosis in male apolipoprotein E-knockout mice
aDivision of Rheumatology, Department of Internal Medicine, University Hospital of Geneva, Switzerland
bDepartment of Pathology and Immunology, University of Geneva School of Medicine, Switzerland
cDivision of Cardiology, Department of Internal Medicine, University Hospital of Geneva, Switzerland
dDivision of Diabetes, Endocrinology and Nutrition, Department of Internal Medicine, University Hospital of Geneva, Switzerland
* Corresponding author. Division of Rheumatology, Department of Internal Medicine, University Hospital of Geneva, 26 avenue Beau Séjour, 1211 Geneva 14, Switzerland. Tel.: +41 22 3823500; fax: +41 22 3823509. Email address: cem.gabay{at}hcuge.ch
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.
KEYWORDS Atherosclerosis; Cytokines; Inflammation
* This work was supported by the Swiss National Science Foundation grants (PP00A-68883 and 3100-067777.02 to BRK), (3200-065121 and 3231-054964.98 to FM), and (3200-054955.98 and 3231-05454.98 to CG). FMS was supported by a postdoctoral grant from the Roche Research Foundation.
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