title: Tumor necrosis factor-related apoptosis-inducing ligand on NK cells protects from hepatic ischemia-reperfusion injury.
abstract: BACKGROUND
  Ischemia-reperfusion injury (IRI) significantly contributes to graft dysfunction after liver transplantation. Natural killer (NK) cells are crucial innate effector cells in the liver and express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a potent inducer of hepatocyte cell death. Here, we investigated if TRAIL expression on NK cells contributes to hepatic IRI.
  
  
  METHODS
  The outcome after partial hepatic IRI was assessed in TRAIL-null mice and contrasted to C57BL/6J wild-type mice and after NK cell adoptive transfer in RAG2/common gamma-null mice that lack T, B, and NK cells. Liver IRI was assessed by histological analysis, alanine aminotransferase, hepatic neutrophil activation by myeloperoxidase activity, and cytokine secretion at specific time points. NK cell cytotoxicity and differentiation were assessed in vivo and in vitro.
  
  
  RESULTS
  Twenty-four hours after reperfusion, TRAIL-null mice exhibited significantly higher serum transaminases, histological signs of necrosis, neutrophil infiltration, and serum levels of interleukin-6 compared to wild-type animals. Adoptive transfer of TRAIL-null NK cells into immunodeficient RAG2/common gamma-null mice was associated with significantly elevated liver damage compared to transfer of wild-type NK cells. In TRAIL-null mice, NK cells exhibit higher cytotoxicity and decreased differentiation compared to wild-type mice. In vitro, cytotoxicity against YAC-1 and secretion of interferon gamma by TRAIL-null NK cells were significantly increased compared to wild-type controls.
  
  
  CONCLUSIONS
  These experiments reveal that expression of TRAIL on NK cells is protective in a murine model of hepatic IRI through modulation of NK cell cytotoxicity and NK cell differentiation.
authors.affiliation: 1 Division of Visceral Surgery and Medicine, University Hospital of Bern, Bern, Switzerland. 2 Department of Clinical Research, University of Bern, Bern, Switzerland. 3 Division of Immunopathology, Institute of Pathology, University Hospital of Bern, Bern, Switzerland. 4 Department of Biology, University of Konstanz, Konstanz, Germany. 5 Address correspondence to: Guido Beldi, M.D., Division of Visceral Surgery and Medicine, University Hospital Bern, CH-3010 Bern, Switzerland.
authors.forename: René
authors.initials: R
authors.lastname: Fahrner
authors.forename: Markus
authors.initials: M
authors.lastname: Trochsler
authors.forename: Nadia
authors.initials: N
authors.lastname: Corazza
authors.forename: Nadine
authors.initials: N
authors.lastname: Graubardt
authors.forename: Adrian
authors.initials: A
authors.lastname: Keogh
authors.forename: Daniel
authors.initials: D
authors.lastname: Candinas
authors.forename: Thomas
authors.initials: T
authors.lastname: Brunner
authors.forename: Deborah
authors.initials: D
authors.lastname: Stroka
authors.forename: Guido
authors.initials: G
authors.lastname: Beldi
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016923:Cell Death; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D006098:Granulocytes / Q000166:cytology; D022781:Hepatocytes / Q000166:cytology; D015850:Interleukin-6 / Q000097:blood; D007694:Killer Cells, Natural / Q000166:cytology / Q000378:metabolism*; D008099:Liver / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis / Q000473:pathology; D009504:Neutrophils / Q000166:cytology; D018384:Oxidative Stress; D009195:Peroxidase / Q000378:metabolism; D015427:Reperfusion Injury / Q000473:pathology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism / Q000502:physiology*; D000637:Transaminases / Q000097:blood
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D009195:Peroxidase; D000637:Transaminases