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J Hepatol. 2006 Jul;45(1):60-71. Epub 2006 Feb 8.

Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC.

Author information

1
Division of Medicine, Liver and Gastroenterology Units, Hadassah University Hospital, Pob 12000, 91120 Jerusalem, Israel.

Abstract

BACKGROUND/AIMS:

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.

PMID:
16515819
DOI:
10.1016/j.jhep.2005.12.025
[Indexed for MEDLINE]

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