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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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 and Gregory J. Gores
Journal of Pharmacology and Experimental Therapeutics November 2002, 303 (2) 461-467; DOI: https://doi.org/10.1124/jpet.102.040030
Hajime Higuchi
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Steven F. Bronk
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Makiko Taniai
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Ali Canbay
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Gregory J. Gores
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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.

Footnotes

  • This work was supported by grants from the National Institutes of Health (DK41876), the Palumbo Foundation, Pittsburgh, Penn and by the Mayo Foundation (Rochester, MN).

  • DOI: 10.1124/jpet.102.040030

  • Abbreviations:
    TRAIL
    tumor necrosis factor-related apoptosis-inducing ligand
    TNF
    tumor necrosis factor
    FADD
    Fas-associated death domain
    DISC
    death-inducing signaling complex
    BDL
    bile duct ligation
    PAGE
    polyacrylamide gel electrophoresis
    ALT
    alanine aminotransferase
    TUNEL
    terminal deoxynucleotidyl transferase dUTP nick-end labeling
    PCR
    polymerase chain reaction
    PMSF
    phenylmethylsulfonyl fluoride
    CHAPS
    3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid
    DR
    death receptor
    • Received June 4, 2002.
    • Accepted July 2, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 303 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 303, Issue 2
1 Nov 2002
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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 and Gregory J. Gores
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 461-467; DOI: https://doi.org/10.1124/jpet.102.040030

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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 and Gregory J. Gores
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 461-467; DOI: https://doi.org/10.1124/jpet.102.040030
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