Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore.
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Life Sci Alliance. 2021 Jan 29;4(4). doi: 10.26508/lsa.202000803. Print 2021 Apr.
Hepatocytes and liver-resident macrophages known as Kupffer cells (KCs) are key cell types involved in liver fibrosis. The transcription factor c-Jun plays a fundamental role in regulating hepatocyte and macrophage functions. We have examined c-Jun's role in the functional interaction of these cells during liver fibrosis induced by carbon tetrachloride. While hepatocyte-specific deletion led to increased fibrosis, the opposite outcome was observed when was deleted in both hepatocytes and KCs. Molecular analyses revealed compromised cytokine gene expression as the apical event related to the phenotype. Yet, purified hepatocytes from both mouse cohorts showed similar defects in cytokine gene expression. However, we noted increased macrophage infiltration in the absence of c-Jun in hepatocytes, which when chemically depleted, reversed the phenotype. Consistently, deletion in KCs alone also led to reduced fibrosis and cytokine gene expression. By contrast, deletion in hepatocytes and KCs did not affect the resolution phase after fibrotic injury. These data together demonstrate a pro-fibrogenic role for c-Jun in hepatocytes and KCs that functionally interact to regulate liver fibrosis.
肝细胞和肝固有巨噬细胞（又称库普弗细胞）是参与肝纤维化的关键细胞类型。转录因子 c-Jun 在调节肝细胞和巨噬细胞功能方面发挥着重要作用。我们研究了 c-Jun 在四氯化碳诱导的肝纤维化过程中这些细胞之间功能相互作用中的作用。虽然肝细胞特异性缺失导致纤维化增加，但当肝细胞和库普弗细胞中都缺失时，观察到相反的结果。分子分析显示，细胞因子基因表达受损是与表型相关的主要事件。然而，来自两个小鼠队列的纯化肝细胞显示出相似的细胞因子基因表达缺陷。然而，我们注意到在没有 c-Jun 的情况下巨噬细胞浸润增加，而当用化学方法耗尽巨噬细胞时，表型会逆转。同样，仅在库普弗细胞中缺失也会导致纤维化和细胞因子基因表达减少。相比之下，在肝纤维化损伤后的消退阶段，肝细胞和库普弗细胞中缺失 c-Jun 并不影响这一阶段。这些数据共同表明 c-Jun 在肝细胞和库普弗细胞中具有促纤维化作用，它们通过功能相互作用来调节肝纤维化。
