Xie Jieshi, Yang Le, Tian Lei, Li Weiyang, Yang Lin, Li Liying
Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China.
Sci Rep. 2016 Jun 8;6:27665. doi: 10.1038/srep27665.
Macrophage migration inhibitor factor (MIF), a multipotent innate immune mediator, is an upstream component of the inflammatory cascade in diseases such as liver disease. Monocyte chemoattractant protein-1 (MCP-1), a highly representative chemokine, is critical in liver disease pathogenesis. We investigated the role of MIF in regulating hepatocytic MCP-1 expression. MIF and MCP-1 expression were characterized by immunochemistry, RT-PCR, ELISA, and immunoblotting in CCl4-treated mouse liver and isolated hepatocytes. MIF was primarily distributed in hepatocytes, and its expression increased upon acute liver injury. Its expression was also increased in injured hepatocytes, induced by LPS or CCl4, which mimic liver injury in vitro. MIF was expressed earlier than MCP-1, strongly inducing hepatocytic MCP-1 expression. Moreover, the increase in MCP-1 expression induced by MIF was inhibited by CD74- or CD44-specific siRNAs and SB203580, a p38 MAPK inhibitor. Further, CD74 or CD44 deficiency effectively inhibited MIF-induced p38 activation. MIF inhibitor ISO-1 reduced MCP-1 expression and p38 phosphorylation in CCl4-treated mouse liver. Our results showed that MIF regulates MCP-1 expression in hepatocytes of injured liver via CD74, CD44, and p38 MAPK in an autocrine manner, providing compelling information on the role of MIF in liver injury, and implying a new regulatory mechanism for liver inflammation.
巨噬细胞移动抑制因子（MIF）是一种多效性固有免疫介质，是诸如肝病等疾病中炎症级联反应的上游成分。单核细胞趋化蛋白-1（MCP-1）是一种极具代表性的趋化因子，在肝病发病机制中起关键作用。我们研究了MIF在调节肝细胞MCP-1表达中的作用。通过免疫化学、逆转录-聚合酶链反应（RT-PCR）、酶联免疫吸附测定（ELISA）和免疫印迹法，对四氯化碳处理的小鼠肝脏及分离的肝细胞中的MIF和MCP-1表达进行了表征。MIF主要分布于肝细胞中，其表达在急性肝损伤时增加。在脂多糖（LPS）或四氯化碳诱导的体外模拟肝损伤的受损肝细胞中，其表达也增加。MIF的表达早于MCP-1，能强烈诱导肝细胞MCP-1表达。此外，MIF诱导的MCP-1表达增加受到CD74或CD44特异性小干扰RNA（siRNAs）以及p38丝裂原活化蛋白激酶（MAPK）抑制剂SB203580的抑制。此外，CD74或CD44缺陷有效抑制了MIF诱导的p38活化。MIF抑制剂ISO-1降低了四氯化碳处理的小鼠肝脏中MCP-1的表达及p38磷酸化。我们的结果表明，MIF通过CD74、CD44和p38 MAPK以自分泌方式调节受损肝脏肝细胞中MCP-1的表达，为MIF在肝损伤中的作用提供了有力信息，并暗示了一种新的肝脏炎症调节机制。
