Department of Microbiology and Immunology, Centre for Molecular Medicine and Stem Cell Research, Faculty of Medicine, University of Kragujevac, Serbia.
J Hepatol. 2012 Jan;56(1):26-33. doi: 10.1016/j.jhep.2011.03.022. Epub 2011 May 18.
BACKGROUND & AIMS: We used Concanavalin A-induced liver injury to study the role of Interleukin 33 and its receptor ST2 in the induction of inflammatory pathology and hepatocellular damage.
We tested susceptibility to Concanavalin A induced hepatitis in ST2 deficient and wild type BALB/c mice and analyzed the effects of single injection of Interleukin 33 as evaluated by liver enzyme test, quantitative histology, mononuclear cell infiltration, cytokine production, intracellular staining of immune cells, and markers of apoptosis in the liver.
ST2 deficient mice developed significantly more severe hepatitis and had significantly higher number of mononuclear cells in the liver, CD4+ and CD8+ T cells, NKp46+ and CD3+NKp46+ cells, and F4/80+ macrophages. The level of pro-inflammatory cytokines in the sera and number of TNF alpha, IFN gamma, and IL-17 producing cells was higher in ST2 deficient mice. In contrast, number of CD4+Foxp3+ cells was statistically higher in wild type mice. Additionally, treatment of wild type mice with single (1 μg) injection of Interleukin 33 led to attenuation of the liver injury and milder infiltration of mononuclear cells, increase in total number of liver CD4+Foxp3+ cells and IL-4 producing CD4+ T cells. Interleukin 33 also suppressed the activation of caspase 3, prevented the expression of BAX, and enhanced the expression of antiapoptotic Bcl-2 in the liver.
We concluded that Interleukin 33/ST2 axis downregulated Concanavalin A-induced liver injury and should be evaluated as potential target in fulminant hepatitis in humans.
我们利用伴刀豆球蛋白 A 诱导的肝损伤来研究白细胞介素 33 及其受体 ST2 在诱导炎症病理和肝细胞损伤中的作用。
我们在 ST2 缺陷型和野生型 BALB/c 小鼠中检测了对伴刀豆球蛋白 A 诱导的肝炎的易感性，并通过肝酶试验、定量组织学、单核细胞浸润、细胞因子产生、免疫细胞的细胞内染色以及肝内细胞凋亡标志物分析了单次注射白细胞介素 33 的作用。
ST2 缺陷型小鼠发生的肝炎更严重，肝内单核细胞、CD4+和 CD8+T 细胞、NKp46+和 CD3+NKp46+细胞以及 F4/80+巨噬细胞数量明显增加。ST2 缺陷型小鼠血清中促炎细胞因子水平和 TNF-α、IFN-γ和 IL-17 产生细胞数量更高。相反，野生型小鼠中 CD4+Foxp3+细胞数量统计学上更高。此外，野生型小鼠单次（1μg）注射白细胞介素 33 可减轻肝损伤，单核细胞浸润减轻，肝内 CD4+Foxp3+细胞总数和产生 IL-4 的 CD4+T 细胞增加。白细胞介素 33 还抑制了 caspase 3 的激活，防止了 BAX 的表达，并增强了肝内抗凋亡 Bcl-2 的表达。
我们得出结论，白细胞介素 33/ST2 轴下调了伴刀豆球蛋白 A 诱导的肝损伤，应作为人类暴发性肝炎的潜在靶点进行评估。
