Home LiteratureArticle Details
PMID: 18166357 Published · ppublish English Journal Article Research Support, N.I.H., Intramural

Abrogation of the antifibrotic effects of natural killer cells/interferon-gamma contributes to alcohol acceleration of liver fibrosis.

Gastroenterology ·Vol. 134 ·No. 1 ·2008-01-00 ·Pages 248-58

Jeong WI, Park O, Gao B

Abstract

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-gamma (IFN-gamma). 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 (CCl(4)) for 2 weeks. Hepatic stellate cells (HSCs) were also isolated and cultured for in vitro studies. CCl(4) 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-gamma 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-gamma expression on NK cells from ethanol-fed mice. In vitro, HSCs from ethanol-fed mice were resistant to IFN-gamma-induced cell cycle arrest and apoptosis compared with pair-fed mice. Such resistance was due to diminished IFN-gamma 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-beta1 (TGF-beta1) neutralizing antibody. Chronic ethanol consumption attenuates the antifibrotic effects of NK/IFN-gamma/STAT1 in the liver, representing new and different therapeutic targets with which to treat alcoholic liver fibrosis.

MeSH Terms
Alcoholism/complications Animals Cell Culture Techniques Disease Models, Animal Hepatocytes/physiology Interferon Inducers/therapeutic use Interferon-gamma/therapeutic use Killer Cells, Natural/physiology Liver Cirrhosis, Alcoholic/etiology,pathology,prevention & control Male Mice Mice, Inbred C57BL Poly I-C/therapeutic use STAT1 Transcription Factor/physiology
Chemicals
Interferon Inducers STAT1 Transcription Factor Interferon-gamma Poly I-C
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Jeong Won-Il
Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
Park Ogyi
Gao Bin
References (43)
43 references, click to expand
  1. Alcohol use and hepatitis C.
    Hepatology. 2002 Nov;36(5 Suppl 1):S220-5 PMID: 12407597
  2. Intracellular antioxidant activity is necessary to modulate the macrophage response to endotoxin.
    Shock. 2002 Jul;18(1):58-63 PMID: 12095135
  3. Opioid antagonist naltrexone disrupts feedback interaction between mu and delta opioid receptors in splenocytes to prevent alcohol inhibition of NK cell function.
    J Immunol. 2004 Jul 1;173(1):42-9 PMID: 15210757
  4. Suppression of innate immunity by acute ethanol administration: a global perspective and a new mechanism beginning with inhibition of signaling through TLR3.
    J Immunol. 2004 Aug 15;173(4):2715-24 PMID: 15294990
  5. Alcohol and hepatitis C.
    Semin Liver Dis. 2004 Aug;24(3):305-15 PMID: 15349807
  6. Hepatic fibrosis and cirrhosis after chronic administration of alcohol and "low-dose" carbon tetrachloride vapor in the rat.
    Hepatology. 1991 May;13(5):815-9 PMID: 2029987
  7. Immunodeficiency associated with ethanol abuse.
    Adv Exp Med Biol. 1991;288:229-36 PMID: 1950734
  8. Inhibition of rat hepatic lipocyte activation in culture by interferon-gamma.
    Hepatology. 1992 Sep;16(3):776-84 PMID: 1505921
  9. Clinical impact of drug addiction in alcoholics.
    Alcohol Alcohol. 1995 Jan;30(1):55-60 PMID: 7538299
  10. A histopathological study of alcoholics with chronic HCV infection: comparison with chronic hepatitis C and alcoholic liver disease.
    Liver. 1995 Dec;15(6):300-6 PMID: 8609809
  11. Interferon gamma decreases hepatic stellate cell activation and extracellular matrix deposition in rat liver fibrosis.
    Hepatology. 1996 May;23(5):1189-99 PMID: 8621153
  12. Hepatitis C and alcohol.
    Hepatology. 1997 Sep;26(3 Suppl 1):39S-42S PMID: 9305662
  13. Alterations in tumor necrosis factor-alpha, interferon-gamma, and interleukin-6 production by natural killer cell-enriched peripheral blood mononuclear cells in chronic alcoholism: relationship with liver disease and ethanol intake.
    Alcohol Clin Exp Res. 1997 Oct;21(7):1226-31 PMID: 9347083
  14. Transcriptional activation of transforming growth factor beta1 and its receptors by the Kruppel-like factor Zf9/core promoter-binding protein and Sp1. Potential mechanisms for autocrine fibrogenesis in response to injury.
    J Biol Chem. 1998 Dec 11;273(50):33750-8 PMID: 9837963
  15. Alcohol abuse, alcoholism, and damage to the immune system--a review.
    Alcohol Clin Exp Res. 1998 Dec;22(9):1927-42 PMID: 9884135
  16. Stellate cell activation in alcoholic fibrosis--an overview.
    Alcohol Clin Exp Res. 1999 May;23(5):904-10 PMID: 10371412
  17. Transforming growth factor beta and tumor necrosis factor alpha inhibit both apoptosis and proliferation of activated rat hepatic stellate cells.
    Hepatology. 1999 Jul;30(1):196-202 PMID: 10385656
  18. Hepatitis C and alcohol.
    Alcohol Clin Exp Res. 1999 Sep;23(9):1543-51 PMID: 10512322
  19. Liver fibrosis.
    J Clin Invest. 2005 Feb;115(2):209-18 PMID: 15690074
  20. Inhibition of NK cell activity through TGF-beta 1 by down-regulation of NKG2D in a murine model of head and neck cancer.
    J Immunol. 2005 Oct 15;175(8):5541-50 PMID: 16210663
  21. Effect of interferon-gamma on hepatic fibrosis in chronic hepatitis B virus infection: a randomized controlled study.
    Clin Gastroenterol Hepatol. 2005 Aug;3(8):819-28 PMID: 16234012
  22. Ethanol metabolism alters interferon gamma signaling in recombinant HepG2 cells.
    Hepatology. 2005 Nov;42(5):1109-17 PMID: 16250053
  23. The liver as an immunological organ.
    Hepatology. 2006 Feb;43(2 Suppl 1):S54-62 PMID: 16447271
  24. 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 Feb;130(2):435-52 PMID: 16472598
  25. Molecular mechanisms of alcohol-induced hepatic fibrosis.
    Dig Dis. 2005;23(3-4):264-74 PMID: 16508291
  26. Mechanisms of alcohol-induced hepatic fibrosis: a summary of the Ron Thurman Symposium.
    Hepatology. 2006 Apr;43(4):872-8 PMID: 16502397
  27. Interferon gamma-1b for the treatment of fibrosis in chronic hepatitis C infection.
    J Viral Hepat. 2006 May;13(5):322-8 PMID: 16637863
  28. Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC.
    J Hepatol. 2006 Jul;45(1):60-71 PMID: 16515819
  29. Negative regulation of type I interferon signaling: facts and mechanisms.
    Cell Mol Biol (Noisy-le-grand). 2006;52(1):77-87 PMID: 16914099
  30. Chronic ethanol consumption inhibits hepatic natural killer cell activity and accelerates murine cytomegalovirus-induced hepatitis.
    Alcohol Clin Exp Res. 2006 Sep;30(9):1615-23 PMID: 16930225
  31. Global challenges in liver disease.
    Hepatology. 2006 Sep;44(3):521-6 PMID: 16941687
  32. STAT1 inhibits liver fibrosis in mice by inhibiting stellate cell proliferation and stimulating NK cell cytotoxicity.
    Hepatology. 2006 Dec;44(6):1441-51 PMID: 17133483
  33. IFN-gamma abrogates profibrogenic TGF-beta signaling in liver by targeting expression of inhibitory and receptor Smads.
    J Hepatol. 2007 Feb;46(2):295-303 PMID: 17125875
  34. Hepatic fibrosis 2006: report of the Third AASLD Single Topic Conference.
    Hepatology. 2007 Jan;45(1):242-9 PMID: 17187439
  35. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ.
    J Clin Invest. 2007 Mar;117(3):539-48 PMID: 17332881
  36. Final results of a double-blind, placebo-controlled trial of the antifibrotic efficacy of interferon-gamma1b in chronic hepatitis C patients with advanced fibrosis or cirrhosis.
    Hepatology. 2007 Mar;45(3):569-78 PMID: 17326152
  37. Liver: An organ with predominant innate immunity.
    Hepatology. 2008 Feb;47(2):729-36 PMID: 18167066
  38. Hepatitis C and alcohol: interactions, outcomes, and implications.
    J Clin Gastroenterol. 2003 Mar;36(3):242-52 PMID: 12590237
  39. 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 Mar;24(3):291-9 PMID: 10776665
  40. Mechanisms of suppression of poly I:C-induced activation of NK cells by ethanol.
    Alcohol. 2000 May;21(1):87-95 PMID: 10946161
  41. Interferons activate the p42/44 mitogen-activated protein kinase and JAK-STAT (Janus kinase-signal transducer and activator transcription factor) signalling pathways in hepatocytes: differential regulation by acute ethanol via a protein kinase C-dependent mechanism.
    Biochem J. 2000 Jul 15;349(Pt 2):427-34 PMID: 10880341
  42. Stimulation and proliferation of primary rat hepatic stellate cells by cytochrome P450 2E1-derived reactive oxygen species.
    Hepatology. 2002 Jan;35(1):62-73 PMID: 11786960
  43. Cytochrome P450 2E1-derived reactive oxygen species mediate paracrine stimulation of collagen I protein synthesis by hepatic stellate cells.
    J Biol Chem. 2002 Mar 22;277(12):9853-64 PMID: 11782477
Article Info
Journal
Gastroenterology
Abbr.
Gastroenterology
ISSN
1528-0012
DOI
10.1053/j.gastro.2007.09.034
Published
2008-01-00
Epub
2007-00-29
Pages
248-58
Language
English
Region
United States
NLM ID
0374630
PMCID
PMC2923436
Subset
IM
Grants
Intramural NIH HHS · Z99 AA999999 · United States
Intramural NIH HHS · ZIA AA000368-08 · United States
Intramural NIH HHS · ZIA AA000369-08 · United States
Corrections
CommentIn
PMID: 18166364
External Links
PubMed source DOI: 10.1053/j.gastro.2007.09.034 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2