Role of TRAIL and the pro-apoptotic Bcl-2 homolog Bim in acetaminophen-induced liver damage

A Badmann,P Bouillet,T Brunner,T Kaufmann,N Corazza,A Keough

doi:10.1038/cddis.2011.55

Abstract

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.

Highlights

The death mechanism(s) of APAP-induced liver damage is still a matter of debate
Given the critical role of c-Jun N-terminal kinase (JNK) and Bcl-2-interacting mediator of cell death (Bim) in various forms of hepatocyte apoptosis, and the similarity between APAPinduced liver damage and hepatitis mediated by the apoptosis pathway, we explored in this study the role of death receptor-induced JNK and associated Bim activation in APAP-induced liver damage
We have previously shown that TNF-related apoptosis-inducing ligand (TRAIL) synergistically enhances Fas-induced apoptosis in hepatocytes in a JNK-Bim-dependent manner.[9]

Summary

Introduction

The death mechanism(s) of APAP-induced liver damage is still a matter of debate. Clearly, typical signs of both necrotic and apoptotic cell death can be observed. In agreement with the role of Bcl-2 family members in APAP-induced hepatocyte death is that mitochondrial Bax translocation accelerates DNA fragmentation and cell death in APAPinduced liver damage.[7] a critical role of the stress kinase c-Jun N-terminal kinase (Jun kinase, JNK) has been demonstrated in both APAP-induced liver damage[8] and other forms of hepatocyte apoptosis.[9,10,11] APAP treatment leads to JNK activation, and administration of JNK inhibitors have a protective effect on APAP-induced hepatocyte death and associated liver damage. Given the critical role of JNK and Bim in various forms of hepatocyte apoptosis, and the similarity between APAPinduced liver damage and hepatitis mediated by the apoptosis pathway, we explored in this study the role of death receptor-induced JNK and associated Bim activation in APAP-induced liver damage. These findings demonstrate a novel role of the BH3-only protein Bim in APAP-induced liver damage, and further accentuate the role of JNK and Bim in hepatocyte cell death

Methods

Results

Conclusion