Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China.
Department of Thoracic and Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J Hepatol. 2016 Jan;64(1):146-59. doi: 10.1016/j.jhep.2015.08.021. Epub 2015 Aug 31.
BACKGROUND & AIMS: The hallmarks of hepatic ischemia/reperfusion (I/R) injury, a common clinical problem that occurs during liver surgical procedures, include severe cell death and inflammatory responses that contribute to early graft failure and a higher incidence of organ rejection. Unfortunately, effective therapeutic strategies are limited. Tumor necrosis factor receptor (TNFR)-associated factor (TRAF) 3 transduces apoptosis and/or inflammation-related signaling pathways to regulate cell survival and cytokine production. However, the role of TRAF3 in hepatic I/R-induced liver damage remains unknown.
Hepatocyte- or myeloid cell-specific TRAF3 knockdown or transgenic mice were subjected to an I/R model in vivo, and in vitro experiments were performed by treating primary hepatocytes from these mice with hypoxia/reoxygenation stimulation. The function of TRAF3 in I/R-induced liver damage and the potential underlying mechanisms were investigated through various phenotypic analyses and biological approaches.
Hepatocyte-specific, but not myeloid cell-specific, TRAF3 deficiency reduced cell death, inflammatory cell infiltration, and cytokine production in both in vivo and in vitro hepatic I/R models, whereas hepatic TRAF3 overexpression resulted in the opposite effects. Mechanistically, TRAF3 directly binds to TAK1, which enhances the activation of the downstream NF-κB and JNK pathways. Importantly, inhibition of TAK1 almost completely reversed the TRAF3 overexpression-mediated exacerbation of I/R injury.
TRAF3 is a novel hepatic I/R mediator that promotes liver damage and inflammation via TAK1-dependent activation of the JNK and NF-κB pathways. Inhibition of hepatic TRAF3 may represent a promising approach to protect the liver against I/R injury-related diseases.
肝缺血/再灌注（I/R）损伤是一种常见的临床问题，发生在肝脏手术过程中，其特征包括严重的细胞死亡和炎症反应，导致早期移植物失败和器官排斥反应的发生率增加。不幸的是，有效的治疗策略有限。肿瘤坏死因子受体（TNFR）相关因子（TRAF）3 转导细胞凋亡和/或炎症相关信号通路，以调节细胞存活和细胞因子产生。然而，TRAF3 在肝 I/R 诱导的肝损伤中的作用尚不清楚。
在体内 I/R 模型中，采用肝细胞或髓系细胞特异性 TRAF3 敲低或转基因小鼠，并用缺氧/复氧刺激处理来自这些小鼠的原代肝细胞进行体外实验。通过各种表型分析和生物学方法研究 TRAF3 在 I/R 诱导的肝损伤中的作用及其潜在机制。
肝细胞特异性而非髓系细胞特异性 TRAF3 缺失减少了体内和体外肝 I/R 模型中的细胞死亡、炎症细胞浸润和细胞因子产生，而肝 TRAF3 过表达则产生相反的效果。在机制上，TRAF3 直接与 TAK1 结合，增强下游 NF-κB 和 JNK 途径的激活。重要的是，TAK1 的抑制几乎完全逆转了 TRAF3 过表达介导的 I/R 损伤加重。
TRAF3 是一种新的肝 I/R 介质，通过 TAK1 依赖性激活 JNK 和 NF-κB 途径促进肝损伤和炎症。抑制肝 TRAF3 可能是一种有前途的方法，可用于保护肝脏免受 I/R 损伤相关疾病的侵害。
