Department of Surgery, Thomas E Starzl Transplant Institute, University of Pittsburgh, Pittsburgh, PA, USA.
Hepatology. 2010 May;51(5):1692-701. doi: 10.1002/hep.23501.
Interferon regulatory factor-1 (IRF-1) is a transcription factor that regulates gene expression during immunity. We hypothesized that IRF-1 plays a pivotal role in liver transplant (LTx) ischemia/reperfusion (I/R) injury. Mouse orthotopic LTx was conducted after 24 hours cold storage in University of Wisconsin (UW) solution in wildtype (WT) C57BL/6 and IRF-1 knockout (KO) mice. IRF-1 deficiency in liver grafts, but not in recipients, resulted in significant reduction of hepatocyte apoptosis and liver injury, as well as improved survival. IRF-1 mRNA up-regulation was typically seen in graft hepatocytes in WT-->WT LTx. Deficiency of IRF-1 signaling in graft resulted in significantly reduced messenger RNA (mRNA) levels for death ligands and death receptors in hepatocytes, as well as decreased caspase-8 activities, indicating that IRF-1 mediates death ligand-induced hepatocyte death. Further, a smaller but significant IRF-1 mRNA up-regulation was seen in WT graft nonparenchymal cells (NPC) and associated with interferon gamma (IFN-gamma) mRNA up-regulation exclusively in NPC. IFN-gamma mRNA was significantly reduced in IRF-1 KO graft. Thus, IRF-1 in graft hepatocytes and NPC has distinct effects in hepatic I/R injury. However, LTx with chimeric liver grafts showed that grafts lacking hepatocellular IRF-1 had better protection compared with those lacking IRF-1 in NPC. The study identifies a critical role for IRF-1 in liver transplant I/R injury.
干扰素调节因子-1（IRF-1）是一种转录因子，可在免疫过程中调节基因表达。我们假设 IRF-1 在肝移植（LTx）缺血/再灌注（I/R）损伤中发挥关键作用。在野生型（WT）C57BL/6 和 IRF-1 敲除（KO）小鼠中，使用 University of Wisconsin（UW）溶液进行 24 小时冷保存后进行原位 LTx。IRF-1 在肝移植物中的缺失，但不在受者中，导致肝细胞凋亡和肝损伤明显减少，生存率提高。WT-->WT LTx 中可见移植物肝细胞中 IRF-1 mRNA 的上调。在移植物中缺乏 IRF-1 信号会导致肝细胞中死亡配体和死亡受体的信使 RNA（mRNA）水平显著降低，同时还会降低半胱天冬酶-8 的活性，表明 IRF-1 介导死亡配体诱导的肝细胞死亡。此外，在 WT 移植物非实质细胞（NPC）中也观察到较小但显著的 IRF-1 mRNA 上调，与 NPC 中干扰素γ（IFN-γ）mRNA 的上调有关。IRF-1 KO 移植物中的 IFN-γ mRNA 显著减少。因此，IRF-1 在肝移植 I/R 损伤中在肝细胞和 NPC 中具有不同的作用。然而，嵌合肝移植的研究表明，与 NPC 中缺乏 IRF-1 的移植物相比，缺乏肝细胞 IRF-1 的移植物具有更好的保护作用。该研究确定了 IRF-1 在肝移植 I/R 损伤中的关键作用。
