© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice
aDepartment of Medicine at Karolinska Hospital and Center for Molecular Medicine L8:03, Karolinska Institute, SE-17176 Stockholm, Sweden
bINSERM U397, Institut Louis Bugnard, Toulouse, France
cCenter for Metabolism and Endocrinology, Department of Medicine, and Center for Nutrition and Toxicology, Novum, Karolinska Institute at Huddinge University Hospital, Stockholm, Sweden
dCenter for Infectious Medicine, Department of Medicine, Karolinska Institute at Huddinge University Hospital, Stockholm, Sweden
eDepartment of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
goran.hansson{at}cmm.ki.se
* Corresponding author. Tel.: +46-8-5177-3227; fax: +46-8-313-147.
Objective: Atherosclerosis is an inflammatory disease in which T helper 1 (Th1) immunity has been proposed to play an important role. Naïve CD4+ T cells differentiate into interferon-
(IFN-) producing Th1 effector cells when stimulated by interleukin-18 (IL-18) and IL-12. We wanted to directly test whether the Th1 pathway is proatherogenic. Methods: We bred IL-18–/– mice with apolipoprotein E–/– (apoE–/–) mice and assessed atherosclerosis in the aortic root of the offspring. Results: 24-week-old IL-18 deficient apoE–/– mice exhibited substantially reduced lesion size (93 866±11 273 vs. 144 019±9667 µm2 in IL-18+/+xapoE–/– mice, P = 0.005). Lesion cells in compound knockout mice displayed reduced I-Ab expression, implying reduced local IFN- stimulation. These mice also had an increased proportion of 
-SM-actin+ smooth muscle cells, compatible with a more stable lesion phenotype. Immunoglobulin G (IgG) subclass analysis of antibodies to malondialdehyde-modified low density lipoprotein indicated increased Th2 and reduced Th1 helper to B cell antibody production. Surprisingly, serum cholesterol and triglyceride levels were significantly higher in IL-18–/–xapoE–/– mice in spite of their reduced atherosclerosis. However, no changes in lipoprotein cholesterol patterns were registered. Conclusion: These data show reduced atherosclerosis and Th1 activity in spite of increased serum cholesterol in IL-18 deficient apoE–/– mice. They support a proatherogenic role for IL-18.
KEYWORDS Atherosclerosis; Interleukin-18; T cells; Inflammation; Mouse models
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