TRAIL mediates liver injury by the innate immune system in the bile duct–ligated mouse

Authors

  • Alisan Kahraman,

    1. Miles and Shirley Fitterman Center for Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
    2. Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
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  • Fernando J. Barreyro,

    1. Miles and Shirley Fitterman Center for Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
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  • Steven F. Bronk,

    1. Miles and Shirley Fitterman Center for Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
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  • Nathan W. Werneburg,

    1. Miles and Shirley Fitterman Center for Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
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  • Justin L. Mott,

    1. Miles and Shirley Fitterman Center for Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
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  • Yuko Akazawa,

    1. Miles and Shirley Fitterman Center for Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
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  • Howard C. Masuoka,

    1. Miles and Shirley Fitterman Center for Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
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  • Charles L. Howe,

    1. Department of Immunology, Mayo Clinic, Rochester, MN
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  • Gregory J. Gores

    Corresponding author
    1. Miles and Shirley Fitterman Center for Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
    • Mayo Clinic, 200 First Street SW, Rochester, MN 55905
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    • fax: 507-284-0762


  • Potential conflict of interest: Nothing to report.

Abstract

The contribution of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), a death ligand expressed by cells of the innate immune system, to cholestatic liver injury has not been explored. Our aim was to ascertain if TRAIL contributes to liver injury in the bile duct–ligated (BDL) mouse. C57/BL6 wild-type (wt), TRAIL heterozygote (TRAIL+/−), and TRAIL knockout (TRAIL−/−) mice were used for these studies. Liver injury and fibrosis were examined 7 and 14 days after BDL, respectively. Hepatic TRAIL messenger RNA (mRNA) was 6-fold greater in BDL animals versus sham-operated wt animals (P < 0.01). The increased hepatic TRAIL expression was accompanied by an increase in liver accumulation of natural killer 1.1 (NK 1.1)–positive NK and natural killer T (NKT) cells, the predominant cell types expressing TRAIL. Depletion of NK 1.1–positive cells reduced hepatic TRAIL mRNA expression and serum alanine aminotransferase (ALT) values. Consistent with a role for NK/NKT cells in this model of liver injury, stress ligands necessary for their recognition of target cells were also up-regulated in hepatocytes following BDL. Compared to sham-operated wt mice, BDL mice displayed a 13-fold increase in terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling (TUNEL) and an 11-fold increase in caspase 3/7–positive hepatocytes (P < 0.01). The number of TUNEL and caspase 3/7–positive cells was reduced by >80% in BDL TRAIL knockout animals (P < 0.05). Likewise, liver histology, number of bile infarcts, serum ALT values, hepatic fibrosis, and animal survival were also improved in BDL TRAIL−/− animals as compared to wt animals. Conclusion: These observations support a pivotal role for TRAIL in cholestatic liver injury mediated by NK 1.1–positive NK/NKT cells. (HEPATOLOGY 2008.)

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