Immune Netw.  2010 Dec;10(6):181-187. 10.4110/in.2010.10.6.181.

Involvement of Hepatic Innate Immunity in Alcoholic Liver Disease

• Byun JS
• Jeong WI

• KMID: 2150673
• DOI: http://doi.org/10.4110/in.2010.10.6.181

Abstract

Excessive alcohol consumption is one of the critical causative factors leading to alcoholic liver disease (ALD). ALD is characterized by a wide spectrum of liver damage, ranging from simple uncomplicated liver steatosis (fatty liver) to steatohepatitis and liver fibrosis/cirrhosis. It has been believed that the obvious underlying cause for ALD is due to hepatocyte death induced by alcohol itself. However, recent sparkling studies have shown that diverse immune responses contribute to ALD because liver is enriched with numerous immune cells. Especially, a line of evidence has suggested that innate immune cells such as Kupffer cells and natural killer (NK)/NKT cells are significantly involved in the pathogenesis of ALD via production of pro-inflammatory cytokines and other mediators. Indeed, more interestingly, hepatic stellate cells (HSCs), known as a major cell inducing liver steatosis and fibrosis, can be killed by liver NK cells, which could be suppressed by chronic alcohol consumption. In this review, with the view of liver as predominant innate immune organ, we describe the pathogenesis of ALD in which what roles of innate immune cells are and how they are interacting with HSCs.

Keyword

Natural killer cell; Interferon-gamma; Hepatic stellate cell; Steatosis; Steatohepatitis; Fibrosis; Alcohol

MeSH Terms

Alcohol Drinking
Alcoholics
Cytokines
Fatty Liver
Fibrosis
Hepatic Stellate Cells
Hepatocytes
Humans
Immunity, Innate
Interferon-gamma
Killer Cells, Natural
Kupffer Cells
Liver
Liver Diseases, Alcoholic
Cytokines
Interferon-gamma

Figure

• 

  Figure 1 Involvement of innate immune cells and HSCs in alcoholic liver disease (ALD).

Reference

1. Williams R. Global challenges in liver disease. Hepatology. 2006. 44:521–526.

2. O'Shea RS, Dasarathy S, McCullough AJ. Practice Guideline Committee of the American Association for the Study of Liver Diseases. Practice Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease. Hepatology. 2010. 51:307–328.

3. Jeong WI, Gao B. Innate immunity and alcoholic liver fibrosis. J Gastroenterol Hepatol. 2008. 23:Suppl 1. S112–S118.

4. Purohit V, Gao B, Song BJ. Molecular mechanisms of alcoholic fatty liver. Alcohol Clin Exp Res. 2009. 33:191–205.

5. Purohit V, Brenner DA. Mechanisms of alcohol-induced hepatic fibrosis: a summary of the Ron Thurman Symposium. Hepatology. 2006. 43:872–878.

6. Gao B, Jeong WI, Tian Z. Liver: An organ with predominant innate immunity. Hepatology. 2008. 47:729–736.

7. Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology. 2006. 43:2 Suppl 1. S54–S62.

8. Crispe IN. The liver as a lymphoid organ. Annu Rev Immunol. 2009. 27:147–163.

9. Doherty DG, O'Farrelly C. Innate and adaptive lymphoid cells in the human liver. Immunol Rev. 2000. 174:5–20.

10. Jeong WI, Osei-Hyiaman D, Park O, Liu J, Bátkai S, Mukhopadhyay P, Horiguchi N, Harvey-White J, Marsicano G, Lutz B, Gao B, Kunos G. Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver. Cell Metab. 2008. 7:227–235.

11. Jeong WI, Park O, Gao B. Abrogation of the antifibrotic effects of natural killer cells/interferon-gamma contributes to alcohol acceleration of liver fibrosis. Gastroenterology. 2008. 134:248–258.

12. Mandrekar P, Szabo G. Signalling pathways in alcohol-induced liver inflammation. J Hepatol. 2009. 50:1258–1266.

13. Otani K, Korenaga M, Beard MR, Li K, Qian T, Showalter LA, Singh AK, Wang T, Weinman SA. Hepatitis C virus core protein, cytochrome P450 2E1, and alcohol produce combined mitochondrial injury and cytotoxicity in hepatoma cells. Gastroenterology. 2005. 128:96–107.

14. Lieber CS. Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis. Alcohol. 2004. 34:9–19.

15. Crabb DW. Recent developments in alcoholism: the liver. Recent Dev Alcohol. 1993. 11:207–230.

16. Fromenty B, Berson A, Pessayre D. Microvesicular steatosis and steatohepatitis: role of mitochondrial dysfunction and lipid peroxidation. J Hepatol. 1997. 26:Suppl 1. 13–22.

17. Yahagi N, Shimano H, Hasty AH, Matsuzaka T, Ide T, Yoshikawa T, Amemiya-Kudo M, Tomita S, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Osuga J, Harada K, Gotoda T, Nagai R, Ishibashi S, Yamada N. Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lep(ob)/Lep(ob) mice. J Biol Chem. 2002. 277:19353–19357.

18. You M, Matsumoto M, Pacold CM, Cho WK, Crabb DW. The role of AMP-activated protein kinase in the action of ethanol in the liver. Gastroenterology. 2004. 127:1798–1808.

19. Costet P, Legendre C, Moré J, Edgar A, Galtier P, Pineau T. Peroxisome proliferator-activated receptor alpha-isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis. J Biol Chem. 1998. 273:29577–29585.

20. Ip E, Farrell GC, Robertson G, Hall P, Kirsch R, Leclercq I. Central role of PPARalpha-dependent hepatic lipid turnover in dietary steatohepatitis in mice. Hepatology. 2003. 38:123–132.

21. Nagy LE. Recent insights into the role of the innate immune system in the development of alcoholic liver disease. Exp Biol Med (Maywood). 2003. 228:882–890.

22. Bird GL, Sheron N, Goka AK, Alexander GJ, Williams RS. Increased plasma tumor necrosis factor in severe alcoholic hepatitis. Ann Intern Med. 1990. 112:917–920.

23. Lin HZ, Yang SQ, Zeldin G, Diehl AM. Chronic ethanol consumption induces the production of tumor necrosis factor-alpha and related cytokines in liver and adipose tissue. Alcohol Clin Exp Res. 1998. 22:5 Suppl. 231S–237S.

24. Pritchard MT, McMullen MR, Stavitsky AB, Cohen JI, Lin F, Medof ME, Nagy LE. Differential contributions of C3, C5, and decay-accelerating factor to ethanol-induced fatty liver in mice. Gastroenterology. 2007. 132:1117–1126.

25. Ji C, Deng Q, Kaplowitz N. Role of TNF-alpha in ethanol-induced hyperhomocysteinemia and murine alcoholic liver injury. Hepatology. 2004. 40:442–451.

26. Yin M, Wheeler MD, Kono H, Bradford BU, Gallucci RM, Luster MI, Thurman RG. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology. 1999. 117:942–952.

27. Lawler JF Jr, Yin M, Diehl AM, Roberts E, Chatterjee S. Tumor necrosis factor-alpha stimulates the maturation of sterol regulatory element binding protein-1 in human hepatocytes through the action of neutral sphingomyelinase. J Biol Chem. 1998. 273:5053–5059.

28. Endo M, Masaki T, Seike M, Yoshimatsu H. TNF-alpha induces hepatic steatosis in mice by enhancing gene expression of sterol regulatory element binding protein-1c (SREBP-1c). Exp Biol Med (Maywood). 2007. 232:614–621.

29. Kang L, Sebastian BM, Pritchard MT, Pratt BT, Previs SF, Nagy LE. Chronic ethanol-induced insulin resistance is associated with macrophage infiltration into adipose tissue and altered expression of adipocytokines. Alcohol Clin Exp Res. 2007. 31:1581–1588.

30. El-Assal O, Hong F, Kim WH, Radaeva S, Gao B. IL-6-deficient mice are susceptible to ethanol-induced hepatic steatosis: IL-6 protects against ethanol-induced oxidative stress and mitochondrial permeability transition in the liver. Cell Mol Immunol. 2004. 1:205–211.

31. Hong F, Radaeva S, Pan HN, Tian Z, Veech R, Gao B. Interleukin 6 alleviates hepatic steatosis and ischemia/reperfusion injury in mice with fatty liver disease. Hepatology. 2004. 40:933–941.

32. Horiguchi N, Wang L, Mukhopadhyay P, Park O, Jeong WI, Lafdil F, Osei-Hyiaman D, Moh A, Fu XY, Pacher P, Kunos G, Gao B. Cell type-dependent pro- and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury. Gastroenterology. 2008. 134:1148–1158.

33. Radaeva S, Wang L, Radaev S, Jeong WI, Park O, Gao B. Retinoic acid signaling sensitizes hepatic stellate cells to NK cell killing via upregulation of NK cell activating ligand RAE1. Am J Physiol Gastrointest Liver Physiol. 2007. 293:G809–G816.

34. Jeong WI, Park O, Radaeva S, Gao B. STAT1 inhibits liver fibrosis in mice by inhibiting stellate cell proliferation and stimulating NK cell cytotoxicity. Hepatology. 2006. 44:1441–1451.

35. Radaeva S, Sun R, Jaruga B, Nguyen VT, Tian Z, Gao B. 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. 130:435–452.

36. McClain CJ, Barve S, Deaciuc I, Kugelmas M, Hill D. Cytokines in alcoholic liver disease. Semin Liver Dis. 1999. 19:205–219.

37. Szabo G. Consequences of alcohol consumption on host defence. Alcohol Alcohol. 1999. 34:830–841.

38. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006. 124:783–801.

39. Seki E, Brenner DA. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology. 2008. 48:322–335.

40. Uesugi T, Froh M, Arteel GE, Bradford BU, Thurman RG. Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. Hepatology. 2001. 34:101–108.

41. Chow JC, Young DW, Golenbock DT, Christ WJ, Gusovsky F. Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J Biol Chem. 1999. 274:10689–10692.

42. Visintin A, Mazzoni A, Spitzer JA, Segal DM. Secreted MD-2 is a large polymeric protein that efficiently confers lipopolysaccharide sensitivity to Toll-like receptor 4. Proc Natl Acad Sci U S A. 2001. 98:12156–12161.

43. Wright SD, Tobias PS, Ulevitch RJ, Ramos RA. Lipopolysaccharide (LPS) binding protein opsonizes LPS-bearing particles for recognition by a novel receptor on macrophages. J Exp Med. 1989. 170:1231–1241.

44. Uesugi T, Froh M, Arteel GE, Bradford BU, Wheeler MD, Gäbele E, Isayama F, Thurman RG. Role of lipopolysaccharide-binding protein in early alcohol-induced liver injury in mice. J Immunol. 2002. 168:2963–2969.

45. Yin M, Bradford BU, Wheeler MD, Uesugi T, Froh M, Goyert SM, Thurman RG. Reduced early alcohol-induced liver injury in CD14-deficient mice. J Immunol. 2001. 166:4737–4742.

46. Nanji AA, Khettry U, Sadrzadeh SM. Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver (disease). Proc Soc Exp Biol Med. 1994. 205:243–247.

47. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010. 11:373–384.

48. Hritz I, Mandrekar P, Velayudham A, Catalano D, Dolganiuc A, Kodys K, Kurt-Jones E, Szabo G. The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88. Hepatology. 2008. 48:1224–1231.

49. Bautista AP. Neutrophilic infiltration in alcoholic hepatitis. Alcohol. 2002. 27:17–21.

50. Kono H, Rusyn I, Yin M, Gäbele E, Yamashina S, Dikalova A, Kadiiska MB, Connor HD, Mason RP, Segal BH, Bradford BU, Holland SM, Thurman RG. NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease. J Clin Invest. 2000. 106:867–872.

51. Thakur V, Pritchard MT, McMullen MR, Wang Q, Nagy LE. Chronic ethanol feeding increases activation of NADPH oxidase by lipopolysaccharide in rat Kupffer cells: role of increased reactive oxygen in LPS-stimulated ERK1/2 activation and TNF-alpha production. J Leukoc Biol. 2006. 79:1348–1356.

52. Wheeler MD, Kono H, Yin M, Rusyn I, Froh M, Connor HD, Mason RP, Samulski RJ, Thurman RG. Delivery of the Cu/Zn-superoxide dismutase gene with adenovirus reduces early alcohol-induced liver injury in rats. Gastroenterology. 2001. 120:1241–1250.

53. Dasu MR, Devaraj S, Zhao L, Hwang DH, Jialal I. High glucose induces toll-like receptor expression in human monocytes: mechanism of activation. Diabetes. 2008. 57:3090–3098.

54. Park HS, Jung HY, Park EY, Kim J, Lee WJ, Bae YS. Cutting edge: direct interaction of TLR4 with NAD(P)H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-kappa B. J Immunol. 2004. 173:3589–3593.

55. Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev. 2008. 88:125–172.

56. Melhem A, Muhanna N, Bishara A, Alvarez CE, Ilan Y, Bishara T, Horani A, Nassar M, Friedman SL, Safadi R. Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC. J Hepatol. 2006. 45:60–71.

57. Taimr P, Higuchi H, Kocova E, Rippe RA, Friedman S, Gores GJ. Activated stellate cells express the TRAIL receptor-2/death receptor-5 and undergo TRAIL-mediated apoptosis. Hepatology. 2003. 37:87–95.

58. Baroni GS, D'Ambrosio L, Curto P, Casini A, Mancini R, Jezequel AM, Benedetti A. Interferon gamma decreases hepatic stellate cell activation and extracellular matrix deposition in rat liver fibrosis. Hepatology. 1996. 23:1189–1199.

59. Park O, Jeong WI, Wang L, Wang H, Lian ZX, Gershwin ME, Gao B. Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride. Hepatology. 2009. 49:1683–1694.

60. Laso FJ, Madruga JI, Girón JA, López A, Ciudad J, San Miguel JF, Alvarez-Mon M, Orfao A. Decreased natural killer cytotoxic activity in chronic alcoholism is associated with alcohol liver disease but not active ethanol consumption. Hepatology. 1997. 25:1096–1100.

61. Pan HN, Sun R, Jaruga B, Hong F, Kim WH, Gao B. Chronic ethanol consumption inhibits hepatic natural killer cell activity and accelerates murine cytomegalovirus-induced hepatitis. Alcohol Clin Exp Res. 2006. 30:1615–1623.

62. Szabo G, Mandrekar P. A recent perspective on alcohol, immunity, and host defense. Alcohol Clin Exp Res. 2009. 33:220–232.

63. Szabo G, Mandrekar P, Girouard L, Catalano D. Regulation of human monocyte functions by acute ethanol treatment: decreased tumor necrosis factor-alpha, interleukin-1 beta and elevated interleukin-10, and transforming growth factor-beta production. Alcohol Clin Exp Res. 1996. 20:900–907.

64. Jaruga B, Hong F, Kim WH, Sun R, Fan S, Gao B. Chronic alcohol consumption accelerates liver injury in T cell-mediated hepatitis: alcohol disregulation of NF-kappaB and STAT3 signaling pathways. Am J Physiol Gastrointest Liver Physiol. 2004. 287:G471–G479.

65. Minagawa M, Deng Q, Liu ZX, Tsukamoto H, Dennert G. Activated natural killer T cells induce liver injury by Fas and tumor necrosis factor-alpha during alcohol consumption. Gastroenterology. 2004. 126:1387–1399.