Interleukin-33 drives hepatic fibrosis through activation of hepatic stellate cells
Interleukin-33 drives hepatic fibrosis through activation of hepatic stellate cells
复制标题
Interleukin-33通过激活肝星状细胞驱动肝纤维化
DOI：
10.1038/cmi.2016.63
复制
发表时间：
2018-04-01
影响因子：
24.1
通讯作者：
Ryffel, Bernhard
中科院分区：
文献类型：
--
作者：
Tan, Zhongming;Liu, Qianghui;Ryffel, Bernhard
肝纤维化是慢性肝病的后果，可引起发病率和死亡率。白细胞介素-33 （IL-33）是炎症的重要介质，可能参与肝纤维化的发展。在这里，我们研究了IL-33在人类患者和实验性胆管结扎（BDL）诱导的小鼠纤维化中的作用。我们报告了小鼠BDL纤维化模型和肝纤维化患者手术样本中肝脏IL-33表达增加。在缺乏IL-33/ST2受体的小鼠中，肝损伤、炎症细胞浸润和纤维化减少，ST2缺陷小鼠肝星状细胞（hsc）的活化降低。重组IL-33激活从C57BL/6小鼠分离的hsc，导致IL-6、TGF-β、α-SMA和胶原蛋白的表达，在缺乏ST2或通过药理抑制MAPK信号传导的情况下，这些表达被取消。最后，重组IL-33显著增加了假手术BL6小鼠的肝脏炎症，但没有增强bdl诱导的肝脏炎症和纤维化。综上所述，bdl诱导的肝脏炎症和纤维化依赖于hsc中的ST2信号，因此，IL-33/ST2通路可能是人类慢性肝炎和肝纤维化患者的潜在治疗靶点。
Liver fibrosis is a consequence of chronic liver disease, causing morbidity and mortality. Interleukin-33 (IL-33) is a critical mediator of inflammation, which may be involved in the development of liver fibrosis. Here, we investigated the role of IL-33 in human patients and experimental bile-duct ligation (BDL)-induced fibrosis in mice. We report increased hepatic IL-33 expression in the murine BDL model of fibrosis and in surgical samples obtained from patients with liver fibrosis. Liver injury, inflammatory cell infiltration and fibrosis were reduced in the absence of the IL-33/ST2 receptor, and the activation of hepatic stellate cells (HSCs) was decreased in ST2-deficient mice. Recombinant IL-33 activated HSCs isolated from C57BL/6 mice, leading to the expression of IL-6, TGF-β, α-SMA and collagen, which was abrogated in the absence of ST2 or by pharmacological inhibition of MAPK signaling. Finally, administration of recombinant IL-33 significantly increased hepatic inflammation in sham-operated BL6 mice but did not enhance BDL-induced hepatic inflammation and fibrosis. In conclusion, BDL-induced liver inflammation and fibrosis are dependent on ST2 signaling in HSCs, and therefore, the IL-33/ST2 pathway may be a potential therapeutic target in human patients with chronic hepatitis and liver fibrosis.