Cholestasis increases tumor necrosis factor-related apoptotis-inducing ligand (TRAIL)-R2/DR5 expression and sensitizes the liver to trail-mediated cytotoxicity

Hajime Higuchi, Steven F. Bronk, Makiko Taniai, Ali Canbay, Gregory J. Gores

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a potential chemotherapeutic agent for cancer, is not thought to be hepatotoxic. We have recently demonstrated, however, that bile acids increase TRAIL-R2/DR5 expression in a human liver cell line and render these cells susceptible to TRAIL-mediated apoptosis. These data suggest TRAIL may be hepatotoxic in cholestasis. The aim of this study was to directly assess TRAIL hepatotoxicity in bile duct-ligated mice, a model of extrahepatic cholestasis. Bile duct-ligated mice (3 days) were used for these studies. TRAIL-R2/DR5 expression was assessed by real-time and immunoblot analysis. The TRAIL death-inducing signaling complex (DISC) was evaluated by immunoprecipitation and immunoblot techniques. Bile duct ligation increased both liver TRAIL-R2/DR5 mRNA and protein expression (>10-fold). Following TRAIL administration (60 μg/mouse, i.v.) to bile duct ligation (BDL) mice, terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive hepatocytes, liver tissue caspase 3-like activity, and serum alanine aminotransferase values increased significantly compared with vehicle-treated BDL mice. The effect of TRAIL on the liver was direct, as the TRAIL DISC (Fas-associated death domain and procaspase 8 protein) was detected in liver tissue. TRAIL-mediated hepatocyte apoptosis in bile duct-ligated mice was associated with significant hepatotoxicity, as assessed by histopathology, although there was no animal mortality. In conclusion, these data define conditions under which TRAIL is hepatotoxic.

Original languageEnglish (US)
Pages (from-to)461-467
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume303
Issue number2
DOIs
StatePublished - Nov 1 2002

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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