Cholestasis Increases Tumor Necrosis Factor-Related Apoptotis-Inducing Ligand (TRAIL)-R2/DR5 Expression and Sensitizes the Liver to TRAIL-Mediated Cytotoxicity
- 1 November 2002
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in The Journal of pharmacology and experimental therapeutics
- Vol. 303 (2), 461-467
- https://doi.org/10.1124/jpet.102.040030
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.Keywords
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