Journal
HEPATOLOGY
Volume 56, Issue 6, Pages 2353-2362Publisher
WILEY
DOI: 10.1002/hep.25893
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Funding
- INSERM
- Ministere de l'Education Nationale de la Recherche et de la Technologie
- University of Rennes
- Region Bretagne
- Ligue contre le cancer
- SFR BIOSIT
- Government of Pakistan (Higher Education Commission, University of Agriculture, Faisalabad)
- Deutsche Krebshilfe [109988]
- Deutsche Forschungsgemeinschaft [SFB/TRR 57]
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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 (TNF alpha) 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 TNF alpha 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 TNF alpha 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 TNF alpha. (HEPATOLOGY 2012;56:2353-2362)
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