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

Hepatology. 2012 Dec;56(6):2353-62. doi: 10.1002/hep.25893. Epub 2012 Sep 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / chemically induced
  • Acute Lung Injury / metabolism*
  • Animals
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • Concanavalin A
  • Fas Ligand Protein / genetics
  • Fas Ligand Protein / metabolism
  • Galactosamine
  • Gene Expression
  • Hepatitis, Animal / chemically induced
  • Hepatitis, Animal / immunology
  • Hepatitis, Animal / metabolism*
  • Hepatocytes / metabolism
  • Interleukin-33
  • Interleukins / genetics
  • Interleukins / metabolism*
  • Mice
  • Natural Killer T-Cells
  • Perforin / genetics
  • Perforin / metabolism
  • Primary Cell Culture
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Receptors, Tumor Necrosis Factor, Type II / genetics
  • Receptors, Tumor Necrosis Factor, Type II / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / genetics
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Il33 protein, mouse
  • Interleukin-33
  • Interleukins
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • TNF-Related Apoptosis-Inducing Ligand
  • Tnfsf10 protein, mouse
  • Tumor Necrosis Factor-alpha
  • anti-Fas monoclonal antibody
  • Concanavalin A
  • Perforin
  • Galactosamine