title: ARC is a novel therapeutic approach against acetaminophen-induced hepatocellular necrosis.
abstract: OBJECTIVE
  Acetaminophen (AAP) overdose is the most frequent cause of drug-induced liver failure. c-Jun N-terminal kinase (JNK) is thought to play a central role in AAP-induced hepatocellular necrosis. The apoptosis repressor with caspase recruitment domain (ARC) is a death repressor that inhibits death receptor and mitochondrial apoptotic signaling. Here, we investigated ARC's therapeutic effect and molecular mechanisms on AAP-induced hepatocellular necrosis.
  
  
  METHODS
  We tested the in vivo and in vitro effects of ARC fused with the transduction domain of HIV-1 (TAT-ARC) on murine AAP hepatotoxicity.
  
  
  RESULTS
  Treatment with TAT-ARC protein completely abrogated otherwise lethal liver failure induced by AAP overdose in C57BL/6 mice. AAP triggered caspase-independent necrosis, as evidenced by liver histology, elevated serum transaminases, and secreted HMGB1 that was inhibited by ARC. ARC-mediated hepatoprotection was not caused by an alteration of AAP metabolism, but resulted in reduced oxidative stress. AAP overdose led to induction of RIP-dependent signaling with subsequent JNK activation. Ectopic ARC inhibited JNK activation by specific interactions between ARC and JNK1 and JNK2. Importantly, survival of mice was even preserved when ARC therapy was initiated in a delayed manner after AAP administration.
  
  
  CONCLUSIONS
  This work identifies for the first time ARC-JNK-binding with subsequent inhibition of JNK signaling as a specific mechanism of ARC to interfere with AAP-dependent necrosis. Our data suggests that AAP-mediated induction of RIP signaling serves as a critical switch for hepatocellular necrosis. The efficacy of TAT-ARC protein transduction in murine AAP hepatotoxicity suggests its therapeutic potential for reversing AAP intoxication also in humans.
authors.affiliation: Max-Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Junfeng
authors.initials: J
authors.lastname: An
authors.forename: Felix
authors.initials: F
authors.lastname: Mehrhof
authors.forename: Christoph
authors.initials: C
authors.lastname: Harms
authors.forename: Gisela
authors.initials: G
authors.lastname: Lättig-Tünnemann
authors.forename: Sabrina L L
authors.initials: SL
authors.lastname: Lee
authors.forename: Matthias
authors.initials: M
authors.lastname: Endres
authors.forename: Mingyi
authors.initials: M
authors.lastname: Li
authors.forename: Gernot
authors.initials: G
authors.lastname: Sellge
authors.forename: Ana D
authors.initials: AD
authors.lastname: Mandić
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.forename: Stefan
authors.initials: S
authors.lastname: Donath
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D015497:HIV-1; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D009336:Necrosis / Q000139:chemically induced / Q000517:prevention & control; D017382:Reactive Oxygen Species / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D051017:Apoptosis Regulatory Proteins; D009124:Muscle Proteins; C491787:Nol3 protein, mouse; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D000082:Acetaminophen; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D048670:MAP Kinase Kinase 4; D005978:Glutathione