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

Abstract

OBJECTIVE: Atherosclerosis is an inflammatory disease in which T helper 1 (Th1) immunity has been proposed to play an important role. Nai;ve CD4+ T cells differentiate into interferon-gamma (IFN-gamma) 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+/-11273 vs. 144,019+/-9667 microm(2) in IL-18(+/+)xapoE(-/-) mice, P=0.005). Lesion cells in compound knockout mice displayed reduced I-A(b) expression, implying reduced local IFN-gamma stimulation. These mice also had an increased proportion of alpha-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.