Translational Medicine & Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary, University of London, Charterhouse Square, London EC1M 6BQ, UK.
Mol Immunol. 2009 Nov;47(1):37-45. doi: 10.1016/j.molimm.2008.12.032. Epub 2009 Feb 8.
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 Th17-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.
最近的报告显示，辅助性 T 细胞 17（Th17）细胞参与了先前归类为 Th1 介导疾病的各种慢性炎症性疾病的发病机制。白细胞介素 18（IL-18）诱导 Th1 细胞产生干扰素-γ（IFN-γ），后者具有动脉粥样硬化作用，而胆固醇引起动脉粥样硬化，并刺激完整的大鼠主动脉产生前列腺素 E2（PGE2），PGE2 是强烈调节 Th17 的 IL-23 的调节剂。我们想测试 Th17 是否具有动脉粥样硬化作用，以及胆固醇是否可以在缺乏 Th1 细胞的 IL-18 缺陷载脂蛋白 E 敲除（ApoE（-/-））小鼠中诱导替代 Th17 途径，如果给予高胆固醇饮食。5 周龄的 IL-18（+/+）ApoE（-/-）和 IL-18（-/-）ApoE（-/-）小鼠给予高胆固醇饮食（HCD）和 IL-18（-/-）ApoE（-/-）低胆固醇饮食（LCD）的对照同窝仔 12 周。在终点时，对冷冻切片的主动脉弓进行染色以进行病变测量和免疫组织化学分析。我们发现，HCD 上的 IL-18（-/-）ApoE（-/-）小鼠的血清胆固醇和甘油三酯水平显着升高，与 18（+/+）ApoE（-/-）小鼠或 IL-18（-/-）ApoE（-/-）小鼠相比，它们的动脉粥样硬化程度也显着增加在 LCD 上。动脉粥样硬化的增加与 Th17 细胞、产生 IL-23 的血管平滑肌细胞（VSMC）和巨噬细胞的增加以及病变中薄的纤维帽相关，其形态学提示易于破裂的不稳定斑块。在体外，胆固醇显着增强了来自 IL-18（-/-）ApoE（-/-）而不是 IL-18（+/+）ApoE（-/-）主动脉的 VSMC 产生 IL-23 和同型半胱氨酸介导的分泌。这项研究表明，在 IL-18 缺乏的情况下，HCD 中的胆固醇与同型半胱氨酸在机制上协同作用，通过替代的 IL-23/Th17 途径加速动脉粥样硬化，证明了 Th17 在动脉粥样硬化中的新作用。
