Suppression of innate immunity (natural killer cell/interferon-γ) in the advanced stages of liver fibrosis in mice

Liver lymphocytes are enriched in natural killer (NK) cells, which play a crucial role in innate immune responses against tumors and pathogenes.1, 2 Recent studies have demonstrated that NK cells also play an important role in suppressing liver fibrosis via killing activated hepatic stellate cells (HSCs) and producing interferon-γ (IFN-γ) in mice and humans.3-5 IFN-γ not only directly induces HSC apoptosis and cell cycle arrest 6 but also stimulates the cytotoxicity of NK cells against activated HSCs via increasing the number of NK cells and upregulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on NK cells.4, 7 Recently, we have demonstrated that retinol metabolites plays an important role in enhancing the sensitivity of activated HSCs to NK cell killing.8 HSCs store large amounts of vitamin A (retinol) in their cytoplasm. Upon activation, they lose their retinol via either release or metabolism of retinol into retinoic acid, which has been implicated in the pathogenesis of liver fibrogenesis.8-10 Retinoic acid is elevated in the HSCs during activation and upregulates the expression of a variety of genes, including retinoic acid-induced early gene 1 (RAE1), an NK cell activating ligand. RAE1 then activates NK cells and increases the susceptibility of HSCs to NK cell killing.4, 8 Emerging evidence suggests that liver fibrosis can be reversed and prevented either via inhibiting HSC activation and proliferation or inducing HSC apoptosis in various immune cell and cytokines-dependent manners.2-7, 9, 10 Among these mechanisms, NK cells/IFN-γ have been suggested to be one of the most potent negative regulators of liver fibrosis. In vivo activation of NK cells by poly I:C or treatment with IFN-γ ameliorates liver fibrosis induced by carbon tetrachloride (CCl4) or dimethylnitrosamine in rodents.4, 6, 11, 12 In addition, clinical studies have shown that IFN-γ treatment attenuates liver fibrosis in some patients with chronic viral hepatitis B (HBV) and HCV infection.13, 14 However, other clinical trials reported that IFN-γ therapy had no beneficial effects in attenuating the severity of advanced fibrosis and cirrhosis in patients with chronic HCV infection.15 The reasons for these controversial reports are not clear. One of possible explanation may be due to the selection of patients with different degrees of liver diseases. In the present study, we compared the antifibrotic efficacy of NK cells/IFN-γ on early and advanced liver fibrosis in vivo and the effects of NK cells/IFN-γ on the different stages of activated HSCs in vitro.