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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Macrophage migration inhibitory factor (MIF) exerts antifibrotic effects in experimental liver fibrosis via CD74
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Macrophage migration inhibitory factor (MIF) exerts antifibrotic effects in experimental liver fibrosis via CD74

机译：巨噬细胞迁移抑制因子（MIF）通过CD74在实验性肝纤维化中发挥抗纤维化作用

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Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine that has been implicated in various inflammatory diseases. Chronic inflammation is a mainstay of liver fibrosis, a leading cause of morbidity worldwide, but the role of MIF in liver scarring has not yet been elucidated. Here we have uncovered an unexpected antifibrotic role for MIF. Mice genetically deleted in Mif (Mif~/~) showed strongly increased fibrosis in two models of chronic liver injury. Pronounced liver fibrosis in Mif~-/- mice was associated with alterations in fibrosis-relevant genes, but not by a changed intrahepatic immune cell infiltration. Next, a direct impact of MIF on hepatic stellate cells (HSC) was assessed in vitro. Although MIF alone had only marginal effects on HSCs, it markedly inhibited PDGF-induced migration and proliferation of these cells. The inhibitory effects of MIF were mediated by CD74, which we detected as the most abundant known MIF receptor on HSCs. MIF promoted the phosphorylation of AMP-activated protein kinase (AMPK) in a CD74-dependent manner and, in turn, inhibition of AMPK reversed the inhibition of PDGF-induced HSC activation by MIF. The pivotal role of CD74 in MIF-mediated antifibrotic properties was further supported by augmented liver scarring of Cd74~'~ mice. Moreover, mice treated with recombinant MIF displayed a reduced fibrogenic response in vivo. In conclusion, we describe a previously unexplored antifibrotic function of MIF that is mediated by the CD74/AMPK signaling pathway in HSCs. The results imply MIF and CD74 as targets for treatment of liver diseases.
机译：巨噬细胞迁移抑制因子（MIF）是一种多效性炎性细胞因子，已与多种炎性疾病有关。慢性炎症是肝脏纤维化的中流，柱，是世界范围内发病的主要原因，但是MIF在肝脏瘢痕形成中的作用尚未阐明。在这里，我们发现了MIF的意外抗纤维化作用。在两种慢性肝损伤模型中，在Mif中被基因删除的小鼠（Mif〜/〜）显示纤维化明显增加。 Mif〜/-小鼠中明显的肝纤维化与纤维化相关基因的改变有关，但与肝内免疫细胞浸润的改变无关。接下来，在体外评估了MIF对肝星状细胞（HSC）的直接影响。尽管单独的MIF对HSC仅有微不足道的作用，但它明显抑制了PDGF诱导的这些细胞的迁移和增殖。 MIF的抑制作用是由CD74介导的，我们将其检测为HSC上最丰富的已知MIF受体。 MIF以CD74依赖性方式促进AMP活化的蛋白激酶（AMPK）的磷酸化，进而抑制AMPK逆转了MIF对PDGF诱导的HSC活化的抑制作用。 CD74在MIF介导的抗纤维化特性中的关键作用进一步得到了Cd74-/-小鼠肝脏瘢痕形成的支持。此外，用重组MIF处理的小鼠在体内显示出降低的纤维化反应。总之，我们描述了HSC中CD74 / AMPK信号通路介导的MIF先前未开发的抗纤维化功能。结果暗示MIF和CD74作为治疗肝病的靶标。

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