Division of Immunopathology, Institute of Pathology, University of Bern, and Visceral and Transplantation Surgery, University Hospital, Bern, Switzerland.
Cell Death Dis. 2011 Jun 9;2(6):e171. doi: 10.1038/cddis.2011.55.
Acetaminophen (N-acetyl-para-aminophenol (APAP), paracetamol) is a commonly used analgesic and antipyretic agent. Although considered safe at therapeutic doses, accidental or intentional overdose causes acute liver failure characterized by centrilobular hepatic necrosis with high morbidity and mortality. Although many molecular aspects of APAP-induced cell death have been described, no conclusive mechanism has been proposed. We recently identified TNF-related apoptosis-inducing ligand (TRAIL) and c-Jun kinase (JNK)-dependent activation of the pro-apoptotic Bcl-2 homolog Bim as an important apoptosis amplification pathway in hepatocytes. In this study, we, thus, investigated the role of TRAIL, c-JNK and Bim in APAP-induced liver damage. Our results demonstrate that TRAIL strongly synergizes with APAP in inducing cell death in hepatocyte-like cells lines and primary hepatocyte. Furthermore, we found that APAP strongly induces the expression of Bim in a c-JNK-dependent manner. Consequently, TRAIL- or Bim-deficient mice were substantially protected from APAP-induced liver damage. This study identifies the TRAIL-JNK-Bim axis as a novel target in the treatment of APAP-induced liver damage and substantiates its general role in hepatocyte death.
对乙酰氨基酚（N-乙酰-对-氨基酚（APAP），扑热息痛）是一种常用的镇痛药和解热药。尽管在治疗剂量下被认为是安全的，但意外或故意过量会导致急性肝衰竭，其特征是中央小叶肝坏死，发病率和死亡率都很高。尽管已经描述了许多与 APAP 诱导的细胞死亡相关的分子方面，但尚未提出明确的机制。我们最近发现 TNF 相关凋亡诱导配体（TRAIL）和 c-Jun 激酶（JNK）依赖性激活促凋亡 Bcl-2 同源物 Bim 是肝细胞中重要的细胞凋亡放大途径。在这项研究中，我们因此研究了 TRAIL、c-JNK 和 Bim 在 APAP 诱导的肝损伤中的作用。我们的结果表明，TRAIL 与 APAP 强烈协同作用，在肝细胞样细胞系和原代肝细胞中诱导细胞死亡。此外，我们发现 APAP 以 c-JNK 依赖性方式强烈诱导 Bim 的表达。因此，TRAIL 或 Bim 缺陷型小鼠从 APAP 诱导的肝损伤中得到了显著保护。这项研究确定了 TRAIL-JNK-Bim 轴作为治疗 APAP 诱导的肝损伤的新靶点，并证实了其在肝细胞死亡中的一般作用。
