title: TRAIL but not FasL and TNFα, regulates IL-33 expression in murine hepatocytes during acute hepatitis.
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.
  
  
  CONCLUSIONS
  The expression of IL-33 during acute hepatitis is dependent on TRAIL, but not on FasL or TNFα.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement et Travail (IRSET), Rennes, France.
authors.forename: Muhammad Imran
authors.initials: MI
authors.lastname: Arshad
authors.forename: Claire
authors.initials: C
authors.lastname: Piquet-Pellorce
authors.forename: Annie
authors.initials: A
authors.lastname: L'Helgoualc'h
authors.forename: Michel
authors.initials: M
authors.lastname: Rauch
authors.forename: Solène
authors.initials: S
authors.lastname: Patrat-Delon
authors.forename: Frédéric
authors.initials: F
authors.lastname: Ezan
authors.forename: Catherine
authors.initials: C
authors.lastname: Lucas-Clerc
authors.forename: Sabrina
authors.initials: S
authors.lastname: Nabti
authors.forename: Agnès
authors.initials: A
authors.lastname: Lehuen
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Cubero
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Girard
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.forename: Michel
authors.initials: M
authors.lastname: Samson
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D003208:Concanavalin A; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism; D005688:Galactosamine; D015870:Gene Expression; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D055611:Natural Killer T-Cells; D054353:Perforin / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C411023:anti-Fas monoclonal antibody; D003208:Concanavalin A; D054353:Perforin; D005688:Galactosamine