Objectives

Amphiregulin (Areg), a glycoprotein from the epidermal growth factor receptor (EGFR) ligand family, has a well-documented protective role against tissue injury; however, its effects on immune-mediated liver injury are still unclear. Here, we used a concanavalin A (ConA)-induced acute liver hepatitis model to explore the effects of Areg on immune-mediated acute liver injury.

Materials and methods

Some C57BL/6 mice were administered ConA at a dose of 20 mg/kg (model mice), and some received 5 µg of Areg (treated mice). Then, their survival rates over 36 h were analyzed. After 5 h of treatment, liver function, hepatic histology, and apoptosis in liver tissue were investigated, and cytokine expression and neutrophil infiltration and activity in the liver were detected. Moreover, the protective effects of Areg were also evaluated without IL-22 in vivo.

Results

Our results showed that Areg administration increased acute liver failure (ALF) mouse survival, restored liver function, and alleviated liver damage. Interestingly, Areg administration increased IL-22 production in hepatic T cells and upregulated IL-22 concentrations in the serum and liver, whereas IL-22 neutralization completely abolished the therapeutic effect of Areg. Meanwhile, Areg administration was concomitant with increased expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL, which are important in the hepatoprotective mechanism of IL-22.

Conclusions

Areg showed direct protective effects against ConA-induced acute liver injury, which suggests the potential therapeutic application of Areg in immune-mediated ALF.

中文翻译：

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双调蛋白通过 IL-22 减轻刀豆球蛋白 A 诱导的急性肝损伤。

 目标

双调蛋白 (Areg) 是一种来自表皮生长因子受体 (EGFR) 配体家族的糖蛋白，具有充分证明的针对组织损伤的保护作用；然而，其对免疫介导的肝损伤的影响仍不清楚。在这里，我们使用刀豆球蛋白 A (ConA) 诱导的急性肝炎模型来探讨 Areg 对免疫介导的急性肝损伤的影响。

 材料和方法

一些 C57BL/6 小鼠接受 20 mg/kg 剂量的 ConA（模型小鼠），一些接受 5 µg Areg（治疗小鼠）。然后，分析他们36小时内的存活率。治疗5 h后，检测肝功能、肝组织学、肝组织细胞凋亡情况，并检测肝脏细胞因子表达量、中性粒细胞浸润及活性。此外，在体内没有IL-22的情况下也评估了Areg的保护作用。

 结果

我们的结果表明，Areg 给药可增加急性肝衰竭 (ALF) 小鼠的存活率、恢复肝功能并减轻肝损伤。有趣的是，Areg 给药增加了肝 T 细胞中 IL-22 的产生，并上调了血清和肝脏中 IL-22 的浓度，而 IL-22 中和则完全消除了 Areg 的治疗作用。同时，Areg 给药伴随着抗凋亡蛋白 Bcl-2 和 Bcl-xL 表达的增加，这在 IL-22 的保肝机制中很重要。

 结论

Areg 对 ConA 诱导的急性肝损伤表现出直接保护作用，这表明 Areg 在免疫介导的 ALF 中具有潜在的治疗应用。