Gastroenterology

Gastroenterology

Volume 134, Issue 1, January 2008, Pages 248-258
Gastroenterology

Basic–Liver, Pancreas, and Biliary Tract
Abrogation of the Antifibrotic Effects of Natural Killer Cells/Interferon-γ Contributes to Alcohol Acceleration of Liver Fibrosis

https://doi.org/10.1053/j.gastro.2007.09.034Get rights and content

Background & Aims: Chronic alcohol drinking accelerates liver fibrosis in patients with viral hepatitis that cannot be fully explained by ethanol-enhanced liver damage. Here, we identified a novel mechanism by which alcohol accelerates liver fibrosis: inhibition of the antifibrotic effects of natural killer (NK) cells and interferon-γ (IFN-γ). Methods: Alcohol administration was achieved by feeding mice with a liquid diet containing 5% ethanol for 8 weeks. Liver fibrosis was induced by administration of carbon tetrachloride (CCl4) for 2 weeks. Hepatic stellate cells (HSCs) were also isolated and cultured for in vitro studies. Results: CCl4 treatment induced greater fibrosis and less apoptosis of HSCs in ethanol-fed mice compared with pair-fed mice. Polyinosinic-polycytidylic acid (Poly I:C) or IFN-γ treatment inhibited liver fibrosis in pair-fed but not in ethanol-fed mice. Poly I:C activation of NK cell cytotoxicity against HSCs was attenuated in ethanol-fed mice compared with pair-fed mice, which was due to reduced natural killer group 2 member D (NKG2D), tumor necrosis factor-related apoptosis-inducing ligand, and IFN-γ expression on NK cells from ethanol-fed mice. In vitro, HSCs from ethanol-fed mice were resistant to IFN-γ–induced cell cycle arrest and apoptosis compared with pair-fed mice. Such resistance was due to diminished IFN-γ activation of signal transducer and activator of transcription 1 (STAT1) in HSCs from ethanol-fed mice caused by the induction of suppressors of cytokine signaling proteins and the production of oxidative stress. Finally, HSCs from ethanol-fed mice were resistant to NK cell killing, which can be reversed by transforming growth factor-β1 (TGF-β1) neutralizing antibody. Conclusions: Chronic ethanol consumption attenuates the antifibrotic effects of NK/IFN-γ/STAT1 in the liver, representing new and different therapeutic targets with which to treat alcoholic liver fibrosis.

Section snippets

Mice

C57BL/6N mice were purchased from the National Cancer Institute (Frederick, MD). All mice used in the present study were housed in a specific pathogen-free facility and were cared for in accordance with National Institutes of Health guidelines.

Chronic Ethanol Consumption and Liver Fibrosis Induced by CCl4

Male C57BL/6N mice weighing ≈25 g were fed a nutritionally adequate liquid diet containing 5% ethanol or a pair-fed diet in which ethanol was substituted isocalorically with dextrin maltose (BioServ, Frenchtown, NJ). Ethanol was introduced gradually by

Ethanol Feeding Decreases HSC Apoptosis and Accelerates Liver Fibrosis During CCl4-Induced Liver Fibrogenesis

Figure 1A shows that injection with 0.1 mL/kg CCl4 induced higher levels of serum ALT in ethanol-fed mice than in pair-fed mice. To generate similar levels of liver injury in both groups, we injected pair-fed mice with a higher dose of CCl4 (0.25 mL/kg). Our results showed that injection with 0.25 mL/kg CCl4 in pair-fed mice caused a similar elevation of serum ALT levels compared with injecting 0.1 mL/kg CCl4 in ethanol-fed mice (Figure 1A). Next, we compared liver fibrosis in these mice (

Discussion

Chronic alcohol consumption is one of the main causes of accelerated liver fibrosis in patients with viral hepatitis.5, 6, 7, 8, 9 In rodents, ethanol feeding was also shown to accelerate CCl4-induced liver fibrosis.10 It is generally believed that ethanol feeding enhances CCl4 metabolism by induction of cytochrome P450 2E1 expression and, subsequently, enhances CCl4-induced liver injury. Here, we also confirmed that injection of the same dose of CCl4 induced more fibrosis in ethanol-fed mice

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    All authors declare that they have no conflict of interest to disclose.

    Supported by the intramural program of National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health.

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