title: Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC.
abstract: OBJECTIVE
  We have investigated the role of natural killer (NK) cells in hepatic fibrogenesis. Mouse NK cells express both inhibitory/activating-killing-immunoglobulin-related-receptors (iKIR/aKIR) specific for Class-I-molecules.
  
  
  METHODS
  Hepatic fibrosis induced by carbon-tetrachloride (CCl4) was compared between wild-type (WT) male-BALBc; combined-immunodeficiency (SCID, lacking B/T-cells); and SCID-BEIGE-mice (lacking B/T/NK cells), and naive mice.
  
  
  RESULTS
  Hepatic fibrosis significantly increased in all CCl4-treated groups. SCID-BEIGE mice had more fibrosis than SCID-mice (P<0.0001) as assessed by morphometry of sirius-red stained tissue sections. Following fibrosis, hepatic NK cells significantly decreased, the aKIR:iKIR-ratio significantly increased while Class-I expression on HSC decreased (P<0.001). Both freshly isolated and in situ HSC displayed a significant increase in cellular apoptosis following fibrosis induction. Confocal microscopy demonstrated the direct adhesion of NK cells to HSC in mouse liver sections and in vitro human NK/HSC co-culture. In human HSC there was decreased Class-I expression and increased apoptosis as well, which was further increased following blocking of either HSC-related Class-I or NK-related killer inhibitory receptors. Apoptosis was inhibited by pre-incubation of NK cells with the granzyme inhibitor 3,4-dichloroisocoumarin.
  
  
  CONCLUSIONS
  During liver injury, NK cells have an anti-fibrotic activity at least in part through stimulation of HSC killing.
authors.affiliation: Division of Medicine, Liver and Gastroenterology Units, Hadassah University Hospital, Pob 12000, 91120 Jerusalem, Israel.
authors.forename: Alaa
authors.initials: A
authors.lastname: Melhem
authors.forename: Nidal
authors.initials: N
authors.lastname: Muhanna
authors.forename: Amal
authors.initials: A
authors.lastname: Bishara
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Alvarez
authors.forename: Yaron
authors.initials: Y
authors.lastname: Ilan
authors.forename: Taiser
authors.initials: T
authors.lastname: Bishara
authors.forename: Amjad
authors.initials: A
authors.lastname: Horani
authors.forename: Mithal
authors.initials: M
authors.lastname: Nassar
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
authors.forename: Rifaat
authors.initials: R
authors.lastname: Safadi
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D002470:Cell Survival; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008103:Liver Cirrhosis / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009130:Muscle, Smooth / Q000276:immunology / Q000473:pathology
chemical_list: D000199:Actins