title: Role of TRAIL and the pro-apoptotic Bcl-2 homolog Bim in acetaminophen-induced liver damage.
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.
authors.affiliation: Division of Immunopathology, Institute of Pathology, University of Bern, and Visceral and Transplantation Surgery, University Hospital, Bern, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Badmann
authors.forename: A
authors.initials: A
authors.lastname: Keough
authors.forename: T
authors.initials: T
authors.lastname: Kaufmann
authors.forename: P
authors.initials: P
authors.lastname: Bouillet
authors.forename: T
authors.initials: T
authors.lastname: Brunner
authors.forename: N
authors.initials: N
authors.lastname: Corazza
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D016923:Cell Death / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000172:deficiency / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D000082:Acetaminophen