Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC.
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.
Melhem
Alaa
A
Division of Medicine, Liver and Gastroenterology Units, Hadassah University Hospital, Pob 12000, 91120 Jerusalem, Israel.
Muhanna
Nidal
N
Bishara
Amal
A
Alvarez
Carlos E
CE
Ilan
Yaron
Y
Bishara
Taiser
T
Horani
Amjad
A
Nassar
Mithal
M
Friedman
Scott L
SL
Safadi
Rifaat
R
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
D000199:Actins