Journal Article

Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice

Rima Elhage, Jacek Jawien, Mats Rudling, Hans-Gustaf Ljunggren, Kiyoshi Takeda, Shizuo Akira, Francis Bayard and Göran K Hansson

in Cardiovascular Research

Published on behalf of European Society of Cardiology

Volume 59, issue 1, pages 234-240
Published in print July 2003 | ISSN: 0008-6363
Published online July 2003 | e-ISSN: 1755-3245 | DOI: http://dx.doi.org/10.1016/S0008-6363(03)00343-2
Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice

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Abstract

Objective: Atherosclerosis is an inflammatory disease in which T helper 1 (Th1) immunity has been proposed to play an important role. Naı̈ve CD4+ T cells differentiate into interferon-γ (IFN-γ) 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+/+×apoE−/− mice, P = 0.005). Lesion cells in compound knockout mice displayed reduced I-Ab expression, implying reduced local IFN-γ stimulation. These mice also had an increased proportion of α-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−/−×apoE−/− 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

Journal Article.  3519 words.  Illustrated.

Subjects: Cardiovascular Medicine

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