TRAIL but not FasL and TNFα, regulates IL-33 expression in murine hepatocytes during acute hepatitis

Authors

  • Muhammad Imran Arshad,

    1. Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement et Travail (IRSET), Rennes, France
    2. Université de Rennes 1, Rennes, France
    3. Fédération de Recherche BioSit de Rennes UMS 3480 CNRS-US18 Inserm, Rennes, France
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  • Claire Piquet-Pellorce,

    1. Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement et Travail (IRSET), Rennes, France
    2. Université de Rennes 1, Rennes, France
    3. Fédération de Recherche BioSit de Rennes UMS 3480 CNRS-US18 Inserm, Rennes, France
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  • Annie L'Helgoualc'h,

    1. Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement et Travail (IRSET), Rennes, France
    2. Université de Rennes 1, Rennes, France
    3. Fédération de Recherche BioSit de Rennes UMS 3480 CNRS-US18 Inserm, Rennes, France
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  • Michel Rauch,

    1. Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement et Travail (IRSET), Rennes, France
    2. Université de Rennes 1, Rennes, France
    3. Fédération de Recherche BioSit de Rennes UMS 3480 CNRS-US18 Inserm, Rennes, France
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  • Solène Patrat-Delon,

    1. Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement et Travail (IRSET), Rennes, France
    2. Université de Rennes 1, Rennes, France
    3. Fédération de Recherche BioSit de Rennes UMS 3480 CNRS-US18 Inserm, Rennes, France
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  • Frédéric Ezan,

    1. Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement et Travail (IRSET), Rennes, France
    2. Université de Rennes 1, Rennes, France
    3. Fédération de Recherche BioSit de Rennes UMS 3480 CNRS-US18 Inserm, Rennes, France
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  • Catherine Lucas-Clerc,

    1. Université de Rennes 1, Rennes, France
    2. Service de Biochimie CHU Rennes, Université de Rennes 1; Rennes, France
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  • Sabrina Nabti,

    1. INSERM U932, Institut Curie, Paris, France
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  • Agnès Lehuen,

    1. INSERM U986, Hôpital Saint Vincent de Paul, Paris, France
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  • Francisco Javier Cubero,

    1. Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany
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  • Jean-Philippe Girard,

    1. Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique (IPBS-CNRS), Université de Toulouse, Toulouse, France
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  • Christian Trautwein,

    1. Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany
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  • Michel Samson

    Corresponding author
    1. Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement et Travail (IRSET), Rennes, France
    2. Université de Rennes 1, Rennes, France
    3. Fédération de Recherche BioSit de Rennes UMS 3480 CNRS-US18 Inserm, Rennes, France
    • INSERM-U1085, IRSET, Université de Rennes 1, 2, Avenue du Professeur Léon Bernard, 35043 Rennes Cedex, France

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  • Potential conflict of interest: Nothing to report.

Abstract

Interleukin (IL)-33, a member of the IL-1 cytokine family, positively correlates with acute hepatitis and chronic liver failure in mice and humans. IL-33 is expressed in hepatocytes and is regulated by natural killer T (NKT) cells during concanavalin A (ConA)-induced acute liver injury. Here, we investigated the molecular mechanisms underlying the expression of IL-33 during acute hepatitis. The expression of IL-33 and its regulation by death receptor pathways was investigated after the induction of ConA-acute hepatitis in wildtype (WT), perforin−/−, tumor necrosis factor related apoptosis inducing ligand (TRAIL)−/−, and NKT cell-deficient (CD1d−/−) mice. In addition, we used a model of acute liver injury by administering Jo2/Fas-antibody or D-galactosamine-tumor necrosis factor alpha (TNFα) in WT mice. Finally, the effect of TRAIL on IL-33 expression was assessed in primary cultured murine hepatocytes. We show that IL-33 expression in hepatocytes is partially controlled by perforin during acute liver injury, but not by TNFα or Fas ligand (FasL). Interestingly, the expression of IL-33 in hepatocytes is blocked during ConA-acute hepatitis in TRAIL-deficient mice compared to WT mice. In contrast, administration of recombinant murine TRAIL associated with ConA-priming in CD1d-deficient mice or in vitro stimulation of murine hepatocytes by TRAIL but not by TNFα or Jo2 induced IL-33 expression in hepatocytes. The IL-33-deficient mice exhibited more severe ConA liver injury than WT controls, suggesting a protective effect of IL-33 in ConA-hepatitis. Conclusion: The expression of IL-33 during acute hepatitis is dependent on TRAIL, but not on FasL or TNFα. (HEPATOLOGY 2012)

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