Silencing a Killer Among Us: Ethanol Impairs Immune Surveillance of Activated Stellate Cells by Natural Killer Cells

Abstract

See “Abrogation of the antifibrotic effects of natural killer cells/interferon-γ contributes to alcohol acceleration of liver fibrosis” by Jeong W–I, Park O, and Gao B, on page 248.Chronic alcoholic liver disease (ALD) affects millions of individuals worldwide each year. The disease process shares a natural history with other chronic liver diseases and is characterized by early steatosis, inflammation, and necrosis. In some individuals, it will ultimately progress to fibrosis and cirrhosis. Although this progression of chronic liver disease is well characterized, there is no universally accepted therapy available to halt or reverse the process in humans. Instead, clinical treatment focuses predominantly on reducing the effects of decompensation caused by cirrhosis and on transplantation.1Diehl A.M. Liver disease in alcohol abusers: clinical perspective.Alcohol. 2002; 27: 7-11Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar A “black box” that has added to difficulties in developing treatments for ALD is that, although the risk of ALD increases in a dose- and time-dependent manner with consumption of alcohol,2Lelbach W.K. Liver damage in chronic alcoholism: results of a clinical, clinical-chemical and bioptic-histological study in 526 alcoholic patients during a low calorie diet in an open drinking sanatorium.Acta Hepatosplenol. 1966; 13: 321-349PubMed Google Scholar, 3Mann R.E. Smart R.G. Govoni R. The epidemiology of alcoholic liver disease.Alcohol Res Health. 2003; 27: 209-219PubMed Google Scholar, 4Mandayam S. Jamal M.M. Morgan T.R. Epidemiology of alcoholic liver disease.Semin Liver Dis. 2004; 24: 217-232Crossref PubMed Scopus (223) Google Scholar only a small proportion of even heavy drinkers develop the severe form of the disease, suggesting the involvement of other factors that modify disease risk.5Day C.P. Who gets alcoholic liver disease: nature or nurture?.J R Coll Physicians Lond. 2000; 34: 557-562PubMed Google Scholar These risk factors may be genetic (eg, polymorphisms in key genes) and/or environmental.A clear environmental risk factor for developing cirrhosis attributable to alcohol consumption is infection with hepatitis C virus (HCV).6Peters M.G. Terrault N.A. Alcohol use and hepatitis C.Hepatology. 2002; 36: S220-S225Crossref PubMed Scopus (0) Google Scholar Interestingly, this increased risk does not appear to be a simple additive effect of the two hepatotoxins; for example, alcohol does not modify the rate of hepatic injury caused by HCV7Uchimura Y. Sata M. Kage M. et al.A histopathological study of alcoholics with chronic HCV infection: comparison with chronic hepatitis C and alcoholic liver disease.Liver. 1995; 15: 300-306Crossref PubMed Scopus (53) Google Scholar in spite of the fact that the rate of fibrosis is enhanced greatly.8Poynard T. Bedossa P. Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups.Lancet. 1997; 349: 825-832Abstract Full Text Full Text PDF PubMed Scopus (2754) Google Scholar, 9Westin J. Lagging L.M. Spak F. et al.Moderate alcohol intake increases fibrosis progression in untreated patients with hepatitis C virus infection.J Viral Hepat. 2002; 9: 235-241Crossref PubMed Scopus (116) Google Scholar, 10Ostapowicz G. Watson K.J. Locarnini S.A. et al.Role of alcohol in the progression of liver disease caused by hepatitis C virus infection.Hepatology. 1998; 27: 1730-1735Crossref PubMed Scopus (239) Google Scholar Whereas this apparent synergy between alcohol and HCV in hepatic fibrogenesis is well-described, mechanisms underlying the relationship remain unclear. In the study by Jeong et al11Jeong W.-I. Park O. Gao B. Abrogation of the antifibrotic effects of natural killer cells/interferon-γ contributes to alcohol acceleration of liver fibrosis.Gastroenterology. 2008; 134: 248-258Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar in this issue, the authors suggest that the synergy between alcohol and HCV may be mediated, at least in part, by impairment of the antifibrotic effects of natural killer (NK) cells.NK cells are members of the innate immune response and comprise up to 50% of the lymphoid pool in the liver. As with other components of the innate immune response, these cells do not express antigen-specific receptors but rather a series of receptors that serve to distinguish “self” from “non-self,” or “altered self.” It is well known that NK cells play a key role in the early immune response against virally infected cells, including HCV-infected hepatocytes.12Biron C.A. Nguyen K.B. Pien G.C. et al.Natural killer cells in antiviral defense: function and regulation by innate cytokines.Annu Rev Immunol. 1999; 17: 189-220Crossref PubMed Scopus (1756) Google Scholar In addition to defending against viral infection, NK cells may also directly ameliorate hepatic fibrosis, first by releasing antifibrotic cytokines (interferon [IFN]α and IFNγ),13Rockey D.C. Chung J.J. Interferon gamma inhibits lipocyte activation and extracellular matrix mRNA expression during experimental liver injury: implications for treatment of hepatic fibrosis.J Investig Med. 1994; 42: 660-670PubMed Google Scholar, 14Inagaki Y. Nemoto T. Kushida M. et al.Interferon alfa down-regulates collagen gene transcription and suppresses experimental hepatic fibrosis in mice.Hepatology. 2003; 38: 890-899Crossref PubMed Google Scholar and second by killing activated stellate cells (see Jeong et al11Jeong W.-I. Park O. Gao B. Abrogation of the antifibrotic effects of natural killer cells/interferon-γ contributes to alcohol acceleration of liver fibrosis.Gastroenterology. 2008; 134: 248-258Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar [Figure 8]).15Radaeva S. Sun R. Jaruga B. et al.Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners.Gastroenterology. 2006; 130: 435-452Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar These lines of defense against injury and fibrosis may be compromised in liver disease. It has been shown in clinical studies that NK cell numbers decrease in HCV infection, but that NK cell cytolytic activity is not impaired.16Morishima C. Paschal D.M. Wang C.C. et al.Decreased NK cell frequency in chronic hepatitis C does not affect ex vivo cytolytic killing.Hepatology. 2006; 43: 573-580Crossref PubMed Scopus (148) Google Scholar Should chronic ethanol exposure inhibit the activity of the depleted pool of NK cells, then the liver’s ability to prevent the development of fibrosis would be hampered greatly.The experimental design of the study by Jeong et al11Jeong W.-I. Park O. Gao B. Abrogation of the antifibrotic effects of natural killer cells/interferon-γ contributes to alcohol acceleration of liver fibrosis.Gastroenterology. 2008; 134: 248-258Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar is relatively straightforward. Animals were exposed to an alcohol liquid diet or isocaloric control diet for 8 weeks, followed by injection with carbon tetrachloride (CCl4 3 times per week) for 2 weeks. Not surprisingly, ethanol preexposure dramatically enhanced liver damage caused by CCl4, most likely due to metabolic activation of this toxin by CYPs, especially CYP2E1. The authors therefore titrated down the dose of CCl4 used in ethanol-exposed mice to match transaminases release observed in the pair-fed controls (0.1 mL/kg vs. 0.25 mL/kg, respectively). Despite similar liver damage at these doses of CCl4, ethanol preexposure significantly enhanced indices of fibrosis (alpha smooth muscle actin [αSMA] expression, collagen staining, and hydroxyproline levels) and decreased the number of apoptotic stellate cells that were observed.The authors next showed that poly I:C (an activator of NK cells) did not decrease fibrosis in alcohol-preexposed mice, whereas it effectively decreased fibrosis in pair-fed mice. The subsequent experiments were designed to determine the mechanisms by which this effect of poly I:C is mediated by ethanol. Using a combination of in vivo, ex vivo, and in vitro experiments, the authors show that ethanol impairs the ability of NK cells to kill stellate cells, both by inhibiting activation and release of cytotoxic mediators in NK cells, as well as by blunting apoptosis in hepatic stellate cell (HSCs) in response to these cytotoxic mediators. Unlike in the initial studies investigating the effect of ethanol on CCl4-induced fibrosis, the authors did not decrease the dose of CCl4 in the ethanol-exposed group to match transaminases with pair-fed controls, which may have induced artifactual differences between the groups. Nevertheless, these data provide a convincing story indicating that ethanol impairs the ability of NK cells to kill activated stellate cells, which would as a result remove this break in the development of fibrosis. Indeed, the strength of this work is the multiple levels of investigation used to test and validate the authors’ underlying hypotheses.What are less convincing are the experiments, largely co-culture experiments, in which the authors attempt to determine the mechanisms by which NK cells are impaired and stellate cells are injured in the alcohol model. First, the authors demonstrated that ethanol increases transforming growth factor-β (TGFβ) production from stellate cells activated in culture, which can then impair the activation of NK cells. Second, they demonstrate that SOCS1, which inhibits IFNγ-induced HSC cell apoptosis via STAT1 signaling, is increased in stellate cells isolated from ethanol exposed mice. Whereas it is certainly possible that these mechanisms are functional in vivo, these co-culture experiments may miss other mechanisms that are important in vivo. For example, work by Pruett et al17Hebert P. Pruett S.B. Ethanol decreases natural killer cell activation but only minimally affects anatomical distribution after administration of polyinosinic:polycytidylic acid: role in resistance to B16F10 melanoma.Alcohol Clin Exp Res. 2003; 27: 1622-1631Crossref PubMed Scopus (9) Google Scholar has shown that acute ethanol impairs lysis and clearance of B16F10 melanoma cells by NK cells in mice. This effect of acute ethanol is mediated, at least in part, by inducing stress hormones (eg, corticosterone) that decrease both basal and stimulated NK lytic function.18Wu W.J. Pruett S.B. Involvement of catecholamines and glucocorticoids in ethanol-induced suppression of splenic natural killer cell activity in a mouse model for binge drinking.Alcohol Clin Exp Res. 1997; 21: 1030-1036Crossref PubMed Scopus (35) Google Scholar, 19Collier S.D. Wu W.J. Pruett S.B. Ethanol suppresses NK cell activation by polyinosinic-polycytidylic acid (poly I:C) in female B6C3F1 mice: role of endogenous corticosterone.Alcohol Clin Exp Res. 2000; 24: 291-299Crossref PubMed Google Scholar Although the effect of chronic ethanol on NK function has not been determined previously, it is known that feeding rodents ethanol chronically under conditions similar to those used by Jeong et al11Jeong W.-I. Park O. Gao B. Abrogation of the antifibrotic effects of natural killer cells/interferon-γ contributes to alcohol acceleration of liver fibrosis.Gastroenterology. 2008; 134: 248-258Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar will increase plasma corticosterone levels.There is no ideal rodent model of fibrosis. Thus, the results may be specific to the model used and not the disease it is modeling. For example, transaminase values in both HCV- and ethanol-induced liver disease are often normal or only slightly elevated, unlike the significant elevations observed with CCl4 administration. The massive hepatocyte death induced in the CCl4 model may itself stimulate the immune response, and thereby overemphasize the role of immune cells relative to other mechanisms underlying liver disease. This concern is compounded by the fact that the immune system may be altered directly by CCl4 exposure.20Jirova D. Sperlingova I. Halaskova M. et al.Immunotoxic effects of carbon tetrachloride—the effect on morphology and function of the immune system in mice.Cent Eur J Public Health. 1996; 4: 16-20PubMed Google Scholar The authors’ findings might be corroborated in a separate rodent model of fibrosis.The implications of this work are expansive. First, these results offer rational explanations as to why the rate of fibrosis in HCV patients is accelerated by alcohol consumption. Furthermore, although it is not possible to test in the CCl4 model, it is likely that ethanol will also blunt immune surveillance by NK cells against virally infected hepatocytes, which would increase viral load and likely exacerbate the disease. Lastly, the finding that ethanol blocks IFNγ-induced HSC apoptosis suggests that some of the beneficial effects of interferon-based antiviral therapies in HCV-induced fibrosis will be attenuated in the setting of coexisting ALD. The mechanisms identified here also have implications beyond ethanol and HCV. For example NK (and NK T cell) function may be altered in other chronic liver diseases (eg, nonalcoholic fatty liver disease).21Li Z. Diehl A.M. Innate immunity in the liver.Curr Opin Gastroenterol. 2003; 19: 565-571Crossref PubMed Scopus (94) Google Scholar Furthermore, previous work has demonstrated a correlation between NK cell depletion and the development of HCC in cirrhotics,22Nakajima T. Mizushima N. Kanai K. Relationship between natural killer activity and development of hepatocellular carcinoma in patients with cirrhosis of the liver.Jpn J Clin Oncol. 1987; 17: 327-332PubMed Google Scholar supporting the role of NK cells in immune surveillance against cancer.23Diefenbach A. Raulet D.H. The innate immune response to tumors and its role in the induction of T-cell immunity.Immunol Rev. 2002; 188: 9-21Crossref PubMed Scopus (179) Google Scholar Indeed, mouse strains deficient in NK cell products or IFNγ-dependent signaling have high rates of developing spontaneous and induced tumors.24Kaplan D.H. Shankaran V. Dighe A.S. et al.Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice.Proc Natl Acad Sci U S A. 1998; 95: 7556-7561Crossref PubMed Scopus (1149) Google Scholar, 25Smyth M.J. Thia K.Y. Street S.E. et al.Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma.J Exp Med. 2000; 192: 755-760Crossref PubMed Scopus (425) Google Scholar The impairment of NK cell functionality and signaling by ethanol may therefore not only enhance the risk of developing cirrhosis, but also the risk of subsequently developing HCC. See “Abrogation of the antifibrotic effects of natural killer cells/interferon-γ contributes to alcohol acceleration of liver fibrosis” by Jeong W–I, Park O, and Gao B, on page 248. See “Abrogation of the antifibrotic effects of natural killer cells/interferon-γ contributes to alcohol acceleration of liver fibrosis” by Jeong W–I, Park O, and Gao B, on page 248. See “Abrogation of the antifibrotic effects of natural killer cells/interferon-γ contributes to alcohol acceleration of liver fibrosis” by Jeong W–I, Park O, and Gao B, on page 248. Chronic alcoholic liver disease (ALD) affects millions of individuals worldwide each year. The disease process shares a natural history with other chronic liver diseases and is characterized by early steatosis, inflammation, and necrosis. In some individuals, it will ultimately progress to fibrosis and cirrhosis. Although this progression of chronic liver disease is well characterized, there is no universally accepted therapy available to halt or reverse the process in humans. Instead, clinical treatment focuses predominantly on reducing the effects of decompensation caused by cirrhosis and on transplantation.1Diehl A.M. Liver disease in alcohol abusers: clinical perspective.Alcohol. 2002; 27: 7-11Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar A “black box” that has added to difficulties in developing treatments for ALD is that, although the risk of ALD increases in a dose- and time-dependent manner with consumption of alcohol,2Lelbach W.K. Liver damage in chronic alcoholism: results of a clinical, clinical-chemical and bioptic-histological study in 526 alcoholic patients during a low calorie diet in an open drinking sanatorium.Acta Hepatosplenol. 1966; 13: 321-349PubMed Google Scholar, 3Mann R.E. Smart R.G. Govoni R. The epidemiology of alcoholic liver disease.Alcohol Res Health. 2003; 27: 209-219PubMed Google Scholar, 4Mandayam S. Jamal M.M. Morgan T.R. Epidemiology of alcoholic liver disease.Semin Liver Dis. 2004; 24: 217-232Crossref PubMed Scopus (223) Google Scholar only a small proportion of even heavy drinkers develop the severe form of the disease, suggesting the involvement of other factors that modify disease risk.5Day C.P. Who gets alcoholic liver disease: nature or nurture?.J R Coll Physicians Lond. 2000; 34: 557-562PubMed Google Scholar These risk factors may be genetic (eg, polymorphisms in key genes) and/or environmental. A clear environmental risk factor for developing cirrhosis attributable to alcohol consumption is infection with hepatitis C virus (HCV).6Peters M.G. Terrault N.A. Alcohol use and hepatitis C.Hepatology. 2002; 36: S220-S225Crossref PubMed Scopus (0) Google Scholar Interestingly, this increased risk does not appear to be a simple additive effect of the two hepatotoxins; for example, alcohol does not modify the rate of hepatic injury caused by HCV7Uchimura Y. Sata M. Kage M. et al.A histopathological study of alcoholics with chronic HCV infection: comparison with chronic hepatitis C and alcoholic liver disease.Liver. 1995; 15: 300-306Crossref PubMed Scopus (53) Google Scholar in spite of the fact that the rate of fibrosis is enhanced greatly.8Poynard T. Bedossa P. Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups.Lancet. 1997; 349: 825-832Abstract Full Text Full Text PDF PubMed Scopus (2754) Google Scholar, 9Westin J. Lagging L.M. Spak F. et al.Moderate alcohol intake increases fibrosis progression in untreated patients with hepatitis C virus infection.J Viral Hepat. 2002; 9: 235-241Crossref PubMed Scopus (116) Google Scholar, 10Ostapowicz G. Watson K.J. Locarnini S.A. et al.Role of alcohol in the progression of liver disease caused by hepatitis C virus infection.Hepatology. 1998; 27: 1730-1735Crossref PubMed Scopus (239) Google Scholar Whereas this apparent synergy between alcohol and HCV in hepatic fibrogenesis is well-described, mechanisms underlying the relationship remain unclear. In the study by Jeong et al11Jeong W.-I. Park O. Gao B. Abrogation of the antifibrotic effects of natural killer cells/interferon-γ contributes to alcohol acceleration of liver fibrosis.Gastroenterology. 2008; 134: 248-258Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar in this issue, the authors suggest that the synergy between alcohol and HCV may be mediated, at least in part, by impairment of the antifibrotic effects of natural killer (NK) cells. NK cells are members of the innate immune response and comprise up to 50% of the lymphoid pool in the liver. As with other components of the innate immune response, these cells do not express antigen-specific receptors but rather a series of receptors that serve to distinguish “self” from “non-self,” or “altered self.” It is well known that NK cells play a key role in the early immune response against virally infected cells, including HCV-infected hepatocytes.12Biron C.A. Nguyen K.B. Pien G.C. et al.Natural killer cells in antiviral defense: function and regulation by innate cytokines.Annu Rev Immunol. 1999; 17: 189-220Crossref PubMed Scopus (1756) Google Scholar In addition to defending against viral infection, NK cells may also directly ameliorate hepatic fibrosis, first by releasing antifibrotic cytokines (interferon [IFN]α and IFNγ),13Rockey D.C. Chung J.J. Interferon gamma inhibits lipocyte activation and extracellular matrix mRNA expression during experimental liver injury: implications for treatment of hepatic fibrosis.J Investig Med. 1994; 42: 660-670PubMed Google Scholar, 14Inagaki Y. Nemoto T. Kushida M. et al.Interferon alfa down-regulates collagen gene transcription and suppresses experimental hepatic fibrosis in mice.Hepatology. 2003; 38: 890-899Crossref PubMed Google Scholar and second by killing activated stellate cells (see Jeong et al11Jeong W.-I. Park O. Gao B. Abrogation of the antifibrotic effects of natural killer cells/interferon-γ contributes to alcohol acceleration of liver fibrosis.Gastroenterology. 2008; 134: 248-258Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar [Figure 8]).15Radaeva S. Sun R. Jaruga B. et al.Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners.Gastroenterology. 2006; 130: 435-452Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar These lines of defense against injury and fibrosis may be compromised in liver disease. It has been shown in clinical studies that NK cell numbers decrease in HCV infection, but that NK cell cytolytic activity is not impaired.16Morishima C. Paschal D.M. Wang C.C. et al.Decreased NK cell frequency in chronic hepatitis C does not affect ex vivo cytolytic killing.Hepatology. 2006; 43: 573-580Crossref PubMed Scopus (148) Google Scholar Should chronic ethanol exposure inhibit the activity of the depleted pool of NK cells, then the liver’s ability to prevent the development of fibrosis would be hampered greatly. The experimental design of the study by Jeong et al11Jeong W.-I. Park O. Gao B. Abrogation of the antifibrotic effects of natural killer cells/interferon-γ contributes to alcohol acceleration of liver fibrosis.Gastroenterology. 2008; 134: 248-258Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar is relatively straightforward. Animals were exposed to an alcohol liquid diet or isocaloric control diet for 8 weeks, followed by injection with carbon tetrachloride (CCl4 3 times per week) for 2 weeks. Not surprisingly, ethanol preexposure dramatically enhanced liver damage caused by CCl4, most likely due to metabolic activation of this toxin by CYPs, especially CYP2E1. The authors therefore titrated down the dose of CCl4 used in ethanol-exposed mice to match transaminases release observed in the pair-fed controls (0.1 mL/kg vs. 0.25 mL/kg, respectively). Despite similar liver damage at these doses of CCl4, ethanol preexposure significantly enhanced indices of fibrosis (alpha smooth muscle actin [αSMA] expression, collagen staining, and hydroxyproline levels) and decreased the number of apoptotic stellate cells that were observed. The authors next showed that poly I:C (an activator of NK cells) did not decrease fibrosis in alcohol-preexposed mice, whereas it effectively decreased fibrosis in pair-fed mice. The subsequent experiments were designed to determine the mechanisms by which this effect of poly I:C is mediated by ethanol. Using a combination of in vivo, ex vivo, and in vitro experiments, the authors show that ethanol impairs the ability of NK cells to kill stellate cells, both by inhibiting activation and release of cytotoxic mediators in NK cells, as well as by blunting apoptosis in hepatic stellate cell (HSCs) in response to these cytotoxic mediators. Unlike in the initial studies investigating the effect of ethanol on CCl4-induced fibrosis, the authors did not decrease the dose of CCl4 in the ethanol-exposed group to match transaminases with pair-fed controls, which may have induced artifactual differences between the groups. Nevertheless, these data provide a convincing story indicating that ethanol impairs the ability of NK cells to kill activated stellate cells, which would as a result remove this break in the development of fibrosis. Indeed, the strength of this work is the multiple levels of investigation used to test and validate the authors’ underlying hypotheses. What are less convincing are the experiments, largely co-culture experiments, in which the authors attempt to determine the mechanisms by which NK cells are impaired and stellate cells are injured in the alcohol model. First, the authors demonstrated that ethanol increases transforming growth factor-β (TGFβ) production from stellate cells activated in culture, which can then impair the activation of NK cells. Second, they demonstrate that SOCS1, which inhibits IFNγ-induced HSC cell apoptosis via STAT1 signaling, is increased in stellate cells isolated from ethanol exposed mice. Whereas it is certainly possible that these mechanisms are functional in vivo, these co-culture experiments may miss other mechanisms that are important in vivo. For example, work by Pruett et al17Hebert P. Pruett S.B. Ethanol decreases natural killer cell activation but only minimally affects anatomical distribution after administration of polyinosinic:polycytidylic acid: role in resistance to B16F10 melanoma.Alcohol Clin Exp Res. 2003; 27: 1622-1631Crossref PubMed Scopus (9) Google Scholar has shown that acute ethanol impairs lysis and clearance of B16F10 melanoma cells by NK cells in mice. This effect of acute ethanol is mediated, at least in part, by inducing stress hormones (eg, corticosterone) that decrease both basal and stimulated NK lytic function.18Wu W.J. Pruett S.B. Involvement of catecholamines and glucocorticoids in ethanol-induced suppression of splenic natural killer cell activity in a mouse model for binge drinking.Alcohol Clin Exp Res. 1997; 21: 1030-1036Crossref PubMed Scopus (35) Google Scholar, 19Collier S.D. Wu W.J. Pruett S.B. Ethanol suppresses NK cell activation by polyinosinic-polycytidylic acid (poly I:C) in female B6C3F1 mice: role of endogenous corticosterone.Alcohol Clin Exp Res. 2000; 24: 291-299Crossref PubMed Google Scholar Although the effect of chronic ethanol on NK function has not been determined previously, it is known that feeding rodents ethanol chronically under conditions similar to those used by Jeong et al11Jeong W.-I. Park O. Gao B. Abrogation of the antifibrotic effects of natural killer cells/interferon-γ contributes to alcohol acceleration of liver fibrosis.Gastroenterology. 2008; 134: 248-258Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar will increase plasma corticosterone levels. There is no ideal rodent model of fibrosis. Thus, the results may be specific to the model used and not the disease it is modeling. For example, transaminase values in both HCV- and ethanol-induced liver disease are often normal or only slightly elevated, unlike the significant elevations observed with CCl4 administration. The massive hepatocyte death induced in the CCl4 model may itself stimulate the immune response, and thereby overemphasize the role of immune cells relative to other mechanisms underlying liver disease. This concern is compounded by the fact that the immune system may be altered directly by CCl4 exposure.20Jirova D. Sperlingova I. Halaskova M. et al.Immunotoxic effects of carbon tetrachloride—the effect on morphology and function of the immune system in mice.Cent Eur J Public Health. 1996; 4: 16-20PubMed Google Scholar The authors’ findings might be corroborated in a separate rodent model of fibrosis. The implications of this work are expansive. First, these results offer rational explanations as to why the rate of fibrosis in HCV patients is accelerated by alcohol consumption. Furthermore, although it is not possible to test in the CCl4 model, it is likely that ethanol will also blunt immune surveillance by NK cells against virally infected hepatocytes, which would increase viral load and likely exacerbate the disease. Lastly, the finding that ethanol blocks IFNγ-induced HSC apoptosis suggests that some of the beneficial effects of interferon-based antiviral therapies in HCV-induced fibrosis will be attenuated in the setting of coexisting ALD. The mechanisms identified here also have implications beyond ethanol and HCV. For example NK (and NK T cell) function may be altered in other chronic liver diseases (eg, nonalcoholic fatty liver disease).21Li Z. Diehl A.M. Innate immunity in the liver.Curr Opin Gastroenterol. 2003; 19: 565-571Crossref PubMed Scopus (94) Google Scholar Furthermore, previous work has demonstrated a correlation between NK cell depletion and the development of HCC in cirrhotics,22Nakajima T. Mizushima N. Kanai K. Relationship between natural killer activity and development of hepatocellular carcinoma in patients with cirrhosis of the liver.Jpn J Clin Oncol. 1987; 17: 327-332PubMed Google Scholar supporting the role of NK cells in immune surveillance against cancer.23Diefenbach A. Raulet D.H. The innate immune response to tumors and its role in the induction of T-cell immunity.Immunol Rev. 2002; 188: 9-21Crossref PubMed Scopus (179) Google Scholar Indeed, mouse strains deficient in NK cell products or IFNγ-dependent signaling have high rates of developing spontaneous and induced tumors.24Kaplan D.H. Shankaran V. Dighe A.S. et al.Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice.Proc Natl Acad Sci U S A. 1998; 95: 7556-7561Crossref PubMed Scopus (1149) Google Scholar, 25Smyth M.J. Thia K.Y. Street S.E. et al.Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma.J Exp Med. 2000; 192: 755-760Crossref PubMed Scopus (425) Google Scholar The impairment of NK cell functionality and signaling by ethanol may therefore not only enhance the risk of developing cirrhosis, but also the risk of subsequently developing HCC. Abrogation of the Antifibrotic Effects of Natural Killer Cells/Interferon-γ Contributes to Alcohol Acceleration of Liver FibrosisGastroenterologyVol. 134Issue 1PreviewBackground & 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. Full-Text PDF