Increased atherosclerotic lesions and Th17 in interleukin-18 deficient apolipoprotein E-knockout mice fed high-fat diet

Recent reports show T helper 17 (Th17) cells are involved in the pathogenesis of various chronic inflammatory diseases formerly categorized as Th1-mediated disorders. Interleukin-18 (IL-18) induces Th1 cells to produce interferon-gamma (IFN-gamma) which is proatherogenic, while cholesterol causes atherosclerosis and stimulates intact rat aortae to produce prostaglandin E-2 (PGE(2)), a strong regulator of IL-23 that expands Th17. We wanted to test whether Th17 is proatherogenic and whether cholesterol can induce the alternative Th17 pathway in IL-18 deficient apolipoprotein E-knockout (ApoE(-/-)) mice that have reduced Th1 cells, if they are fed high-cholesterol diet. IL-18(+)/(+)ApoE(-/-) and IL-18(-/-)ApoE(-/-) mice aged 5 weeks were fed high-cholesterol diet (HCD) and control littermates of IL-18(-/-)ApoE(-/-) low-cholesterol diet (LCD) for 12 weeks. At termination, cryosectioned aortic arches were stained for lesion measurement and immunohistochemistry. We found that serum cholesterol and triglyceride levels were significantly higher in IL-18(-/-)ApoE(-/-) mice on HCD and they also had significantly increased atherosclerosis compared with 18(+)/(+)ApoE(-/-) mice or IL-18(-/-)ApoE(-/-) mice on LCD. Increased atherosclerosis correlates with enhanced Th-17-cells, IL-23-producing vascular smooth muscle cells (VSMC) and macrophages, and thin fibrous cap in lesions. the morphology indicative of unstable plaques prone to rupture. In vitro, cholesterol significantly enhances VSMCs explanted from IL-18(-/-)ApoE(-/-) but not IL-18(+)/(+)ApoE(-/-) aorta to produce IL-23 and homocysteine mediates secretion. This study suggests that in IL-18 deficiency, cholesterol in HCD synergize mechanistically with homocysteine to accelerate atherosclerosis via the alternative IL-23/Th17 pathway, demonstrating a new role for Th17 in atherosclerosis. (C) 2009 Elsevier Ltd. All rights reserved.