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

Abrogation of the Antifibrotic Effects of Natural Killer Cells/Interferon-γ Contributes to Alcohol Acceleration of Liver Fibrosis

“…First, we and others have shown that NK cells kill activated HSCs, which contributes to HSCs apoptosis during liver fibrogenesis. 16,17 Here, we showed that liver NK cells isolated from ethanol-fed mice had less killing of activated HSCs than those from pair-fed mice (Figure 3), which may contribute to less HSC apoptosis observed in ethanol-fed mice after administration of CCl 4 ( Figure 1). Second, activation of NK cells by poly I:C or IFN-γ inhibited liver fibrosis in pair-fed mice but not in ethanol-fed mice (Figures 2 and 4).…”

“…[13][14][15] Recently, we and others have shown that activation of the innate immune system, natural killer (NK) cells and interferon-γ (IFN-γ), inhibits liver fibrosis. [16][17][18] Moreover, the immunosuppressive effects of ethanol are well documented in alcoholics. 19,20 Thus, we hypothesized that inhibition of NK cell/IFN-γ functioning as mediated by ethanol may be an important mechanism that contributes to ethanol acceleration of liver fibrosis.…”

“…21,22 Although activation of NK cells by double-stranded RNA, polyinosinic-polycytidylic acid (poly I:C), or IFN-γ inhibits liver fibrosis, depletion of NK cells enhances liver fibrosis. 16,17 Amelioration of liver fibrosis by NK cells is accomplished through the direct killing of activated HSCs in natural killer group 2 member D (NKG2D)-, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-, and granzyme-dependent manners. 16,17 NK cells can also inhibit liver fibrosis by production of IFN-γ.…”

“…16,17 Amelioration of liver fibrosis by NK cells is accomplished through the direct killing of activated HSCs in natural killer group 2 member D (NKG2D)-, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-, and granzyme-dependent manners. 16,17 NK cells can also inhibit liver fibrosis by production of IFN-γ. 18 The antifibrotic effects of IFN-γ is well documented in animal studies, which show that IFN-γ inhibits HSC activation and stimulates NK cell killing of activated HSCs in vivo and in vitro.…”

The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways

“…These diverse haplotypes have been broadly split into A and B groupings, with the former having one or no functional activating KIR and the latter having several activating KIR. The B group of haplotypes contains genes associated with chronic HCV infection and poor treatment response, including KIR2DL2 and KIR2DS2, but has a minor protective role against end stage manifestations including cirrhosis and HCC, possibly through the activation of NK cells leading to stellate cell apoptosis in the case of fibrosis 39, 40, 41, 42. Activating KIR, components of the KIR B haplotypes, have been previously shown to have a beneficial effect against HCC development 42.…”