IL-35和IL-12在IL-12p35-/-小鼠腹主动脉瘤模型中的作用和机制研究

Abdominal aortic aneurysm (AAA), like atherosclerosis, is a fatal chronic inflammatory disease characterized by macrophages and T lymphocytes infiltration. However, there is no effective medical therapy for the prevention or treatment of AAA. The anti-inflammatory cytokine interleukin (IL) 35 and the pro-inflammatory cytokine IL-12 belong to the IL-12 family and have the same subunit p35. Evidence showed that p35 knockout abolishes the biological activity of IL-35 and IL-12. Both IL-35 and IL-12 take part in chronic inflammatory disease by regulating the activity of macrophage and T lymphocyte. Our previous studies indicated that IL-35 and IL-12 are involved in atherosclerosis. The pre-experiment found that treatment with angiotensin II infusion resulted in AAA in p35-/- mice. However, the role of IL-35 and IL-12 in AAA formation remains uncertain. In vivo and vitro experiments are going to be performed around the effect and mechanism of IL-35 and IL-12 on inflammatory regulation and AAA formation in p35-/- mice. This study will provide experimental evidence for comprehensive evaluation about IL-35 and IL-12 as targets for the treatment of AAA.

与动脉粥样硬化一样，腹主动脉瘤（AAA）是一种巨噬细胞和T淋巴细胞介导的致命性的慢性炎症性疾病。新型抗炎因子IL-35与促炎因子IL-12同属IL-12家族，两者有共同的p35亚基，均通过调控巨噬细胞和T淋巴细胞活性参与慢性炎症性疾病进程。本课题组的前期研究提示，IL-35和IL-12与动脉粥样硬化性疾病的发生发展密切相关；预实验成功构建一种新型AAA模型：血管紧张素II（Ang II）灌注IL-12p35敲除(p35-/-)小鼠AAA模型。但是，p35-/-小鼠AAA的发生与IL-35或IL-12有何种关系及相关机制仍不清楚。本研究采用Ang II诱导p35-/-小鼠AAA模型，分别给予不同剂量IL-35和IL-12，并在信号通路关键分子进行干预，以阐明IL-35、IL-12调控AAA发生发展的机制，为AAA防治的新思路提供实验依据。

腹主动脉瘤是一类慢性免疫/炎症疾病，多种免疫细胞介导的炎症反应是腹主动脉瘤发生发展的主要作用机制之一，纠正免疫/炎症反应可以延缓腹主动脉瘤的发展进程， 因此被认为是临床腹主动脉瘤防治的新思路。本课题组构建p35敲除小鼠、p40敲除小鼠、p19敲除小鼠、p28敲除小鼠和STAT4敲除小鼠，结合重组IL-12干预等方式，结果显示p35敲除小鼠和p40敲除小鼠给予Ang II灌注可形成腹主动脉瘤，而p19敲除小鼠、p28敲除小鼠无明显腹主动脉瘤形成，p35敲除小鼠的动脉瘤进程可被重组IL-12显著逆转，提示p35敲除取消IL-12生物学效应促进腹主动脉瘤进程；此外，p35敲除小鼠和p40敲除小鼠主动脉树突状细胞的成熟显著增加，移植p35小鼠骨髓细胞显著增加腹主动脉瘤发生率，而取消STAT4通路则显著移植树突状细胞成熟和腹主动脉瘤的发生，提示IL-12p35敲除取消IL-12生物学效应，进而通过STAT4通路促进树突状细胞活化，进而促进腹主动脉瘤的发生。本研究初步阐明 IL-12负向调控腹主动脉瘤的生物学作用，提出以 IL-12 为干预靶点防治动腹主动脉瘤性疾病的新思路，具有一定的理论价值和创新性。