Wen Yankai, Feng Dechun, Wu Hailong, Liu Wenjun, Li Hongjie, Wang Fang, Xia Qiang, Gao Wei-Qiang, Kong Xiaoni
1. State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Department of Liver Surgery, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
2. Laboratory of liver diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA.
Int J Biol Sci. 2015 Aug 21;11(10):1236-47. doi: 10.7150/ijbs.12118. eCollection 2015.
The initial process in liver regeneration after partial hepatectomy involves the recruitment of immune cells and the release of cytokines. Osteopontin (OPN), a pro-inflammatory protein, plays critical roles in immune cell activation and migration. Although OPN has been implicated in the pathogenesis of many liver diseases, the role of OPN in liver regeneration remains obscure. In the present study, we found that serum and hepatic OPN protein levels were significantly elevated in wild-type (WT) mice after partial hepatectomy (PHx) and that bile ductal epithelia were the major cell source of hepatic OPN. Compared to WT mice, OPN knockout (KO) mice exhibited delayed liver regeneration after PHx. This delay in OPN(-/-) mice was attributed to impaired hepatic infiltration of macrophages and neutrophils, decreased serum and hepatic IL-6 levels, and blunted activation of macrophages after PHx. Furthermore, we demonstrate that the attenuated activation of macrophages is at least partially due to decreased hepatic and portal vein LPS levels in OPN(-/-) mice. In response to decreased IL-6 levels, the activation of signal transducer and transcription (Stat) 3 was reduced in hepatocytes of OPN(-/-) mice compared to WT mice after PHx. Consequently, hepatic activation of the downstream direct targets of IL6/Stat3, such as c-fos, c-jun, and c-myc, was also suppressed post-PHx in OPN(-/-) mice compared to WT mice. Collectively, these results support a unique role for OPN during the priming phase of liver regeneration, in which OPN enhances the recruitment of macrophages and neutrophils, and triggers hepatocyte proliferation through Kupffer cell-derived IL-6 release and the downstream activation of Stat3.
部分肝切除术后肝脏再生的初始过程涉及免疫细胞的募集和细胞因子的释放。骨桥蛋白（OPN）是一种促炎蛋白，在免疫细胞激活和迁移中起关键作用。尽管OPN与许多肝脏疾病的发病机制有关，但其在肝脏再生中的作用仍不清楚。在本研究中，我们发现野生型（WT）小鼠部分肝切除（PHx）后血清和肝脏OPN蛋白水平显著升高，并且胆管上皮是肝脏OPN的主要细胞来源。与WT小鼠相比，OPN基因敲除（KO）小鼠在PHx后肝脏再生延迟。OPN基因敲除小鼠的这种延迟归因于巨噬细胞和中性粒细胞的肝脏浸润受损、血清和肝脏IL-6水平降低以及PHx后巨噬细胞的激活减弱。此外，我们证明巨噬细胞激活减弱至少部分是由于OPN基因敲除小鼠肝脏和门静脉LPS水平降低。与WT小鼠相比，在PHx后，OPN基因敲除小鼠肝细胞中信号转导子和转录（Stat）3的激活因IL-6水平降低而减少。因此，与WT小鼠相比，OPN基因敲除小鼠在PHx后肝脏中IL6/Stat3下游直接靶点如c-fos、c-jun和c-myc的激活也受到抑制。总体而言，这些结果支持OPN在肝脏再生启动阶段的独特作用，其中OPN增强巨噬细胞和中性粒细胞的募集，并通过库普弗细胞衍生的IL-6释放和Stat3的下游激活触发肝细胞增殖。
