Institute of Clinical Pharmacy and Pharmaceutical Sciences.
Hepatology. 2014 Sep;60(3):1003-14. doi: 10.1002/hep.27189. Epub 2014 Jun 20.
Interleukin (IL)-20 is a proinflammatory cytokine of the IL-10 family and involved in rheumatoid arthritis, atherosclerosis, stroke, and osteoporosis. However, the pathophysiological roles of IL-20 in liver injury have not been extensively studied. We explored the involvement of IL-20 in liver injury and the therapeutic potential of IL-20 antagonists for treating liver fibrosis. Compared with normal liver tissue from healthy individuals, the amount of IL-20 was much higher in hepatocytes and hepatic stellate cells in liver biopsies from patients with fibrosis, cirrhosis, and hepatocellular carcinoma. Carbon tetrachloride (CCl4) treatment induced IL-20 that further up-regulated the expression of transforming growth factor (TGF)-β1 and p21(WAF1) and resulted in cell cycle arrest in the Clone-9 rat hepatocyte cell line. IL-20 activated quiescent rat hepatic stellate cells (HSCs) and up-regulated TGF-β1 expression. IL-20 also increased TGF-β1, tumor necrosis factor (TNF)-α, and type I collagen (Col-I) expression, and promoted the proliferation and migration of activated HSCs. Serum IL-20 was significantly elevated in mice with short-term and long-term CCl4 -induced liver injury. In mice with short-term liver injury, anti-IL-20 monoclonal antibody (7E) and anti-IL-20 receptor (IL-20R1) monoclonal antibody (51D) attenuated hepatocyte damage caused by CCl4, TGF-β1, and chemokine production. In mice with long-term liver injury, 7E and 51D inhibited CCl4 -induced cell damage, TGF-β1 production, liver fibrosis, HSC activation, and extracellular matrix accumulation, which was caused by the reduced expression of tissue inhibitors of metalloproteinases as well as increased metalloproteinase expression and Col-I production. IL-20R1-deficient mice were protected from short-term and long-term liver injury.
We identified a pivotal role of IL-20 in liver injury and showed that 7E and 51D may be therapeutic for liver fibrosis.
白细胞介素（IL）-20 是白细胞介素 10 家族的促炎细胞因子，与类风湿关节炎、动脉粥样硬化、中风和骨质疏松症有关。然而，IL-20 在肝损伤中的病理生理作用尚未得到广泛研究。我们探讨了 IL-20 在肝损伤中的作用以及 IL-20 拮抗剂治疗肝纤维化的治疗潜力。与健康个体的正常肝组织相比，纤维化、肝硬化和肝细胞癌患者肝活检中的肝细胞和肝星状细胞中 IL-20 的含量要高得多。四氯化碳（CCl4）处理诱导 IL-20，进一步上调转化生长因子（TGF）-β1 和 p21（WAF1）的表达，并导致 Clone-9 大鼠肝细胞系中的细胞周期停滞。IL-20 激活静止的大鼠肝星状细胞（HSCs）并上调 TGF-β1 的表达。IL-20 还增加了 TGF-β1、肿瘤坏死因子（TNF）-α 和 I 型胶原（Col-I）的表达，并促进了活化的 HSCs 的增殖和迁移。短期和长期 CCl4 诱导的肝损伤小鼠的血清 IL-20 水平显著升高。在短期肝损伤的小鼠中，抗 IL-20 单克隆抗体（7E）和抗 IL-20 受体（IL-20R1）单克隆抗体（51D）减弱了 CCl4、TGF-β1 和趋化因子产生引起的肝细胞损伤。在长期肝损伤的小鼠中，7E 和 51D 抑制了 CCl4 诱导的细胞损伤、TGF-β1 产生、肝纤维化、HSC 激活和细胞外基质积聚，这是由于组织金属蛋白酶抑制剂的表达减少以及金属蛋白酶和 Col-I 表达增加所致。IL-20R1 缺陷小鼠对短期和长期肝损伤有保护作用。
我们确定了 IL-20 在肝损伤中的关键作用，并表明 7E 和 51D 可能对肝纤维化具有治疗作用。
