Journal of Hepatology
Volume 50, Issue 6 , Pages 1258-1266 , June 2009

Signalling pathways in alcohol-induced liver inflammation

  • Pranoti Mandrekar

      Affiliations

    • Corresponding Author InformationCorresponding authors. Tel.: +1 508 8565275; fax: +1 508 8564770.
  • ,
  • Gyongyi Szabo

      Affiliations

    • Corresponding Author InformationCorresponding authors. Tel.: +1 508 8565275; fax: +1 508 8564770.

References 

  1. Hines IN, Wheeler MD. Recent advances in alcoholic liver disease III. Role of innate immune responses in alcoholic hepatitis. Am J Physiol Gastrointest Liver Physiol. 2004;287:G310–G314
  2. Fujimoto M, Uemura M, Nakatani Y, Tsujita S, Hoppo K, Tamagawa T, et al. Plasma endotoxin and serum cytokine levels in patients with alcoholic hepatitis: relation to severity of liver disturbance. Alcohol Clin Exp Res. 2000;24:48S–54S
  3. McClain CJ, Cohen DA. Increased tumor necrosis factor production by monocytes in alcoholic hepatitis. Hepatology. 1989;9:349–351
  4. Khoruts A, Stahnke L, McClain CJ, Logan G, Allen J. Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentrations in chronic alcoholic patients. Hepatology. 1991;13:267–276
  5. Thakur V, McMullen MR, Ptritchard MT, Nagy LE. Regulation of macrophage activation in alcoholic liver disease. J Gastroenterol Hepatol. 2007;22:S53–S56
  6. 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
  7. Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol. 2005;17:1–14
  8. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801
  9. Saitoh S, Akashi S, Yamada T, Tanimura N, Kobayashi M, Konno K, et al. Lipid A antagonist, lipid IVa, is distinct from lipid A in interaction with Toll-like receptor 4 (TLR4)-MD-2 and ligand-induced TLR4 oligomerization. Int Immunol. 2004;16:961–969
  10. Chow JC, Young DW, Golenbock DT, Christ WJ, Gusovsky F. Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J Biol Chem. 1999;274:10682–10692
  11. 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 USA. 2001;98:12156–12161
  12. Tobias PS, Soldau K, Ulevitch RJ. Isolation of a lipopolysaccharide-binding acute phase reactant from rabbit serum. J Exp Med. 1986;164:777–793
  13. 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
  14. Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science. 1990;249:1431–1433
  15. Dunne A, O’Neill LA. Adaptor usage and Toll-like receptor signaling specificity. FEBS Lett. 2005;579:3330–3335
  16. Jang Z, Georgel P, Du X, Shamel L, Sovath S, Mudd S, et al. CD14 is required for MyD88-independent LPS signaling. Nat Immunol. 2005;6:565–570
  17. Simazu R, Akashi S, Ogata H, Nagai Y, Fukodome K, Miyake K, et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med. 1999;189:1777–1782
  18. Nagai Y, Akashi S, Nagafuku M, Ogata M, Iwakura Y, Akira S, et al. Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat Immunol. 2002;3:667–672
  19. Giovanni TL, Teghanemt A, Zhang D, Coussens NP, Dockstader W, Ramaswamy S, et al. Isolation of an endotoxin-MD-2 complex that produces Toll-like receptor 4-dependent cell activation of picomolar concentrations. Proc Natl Acad Sci USA. 2004;101:4186–4191
  20. Mitsuzawa H, Nishitani C, Hyakushima N, Shimzu T, Sano H, Matsushima N, et al. Recombinant soluble forms of extracellular TLR4 domain and MD-2 inhibit lipopolysaccharide binding on cell surface and dampen lipopolysaccharide-induced pulmonary inflammation in mice. J Immunol. 2006;177:8133–8139
  21. Szabo G, Dolganiuc A, Mandrekar P. Pattern recognition receptors. Hepatology. 2006;44:287–298
  22. Seki E, Brenner DA. TLRs and adaptor molecules in liver disease: update. Hepatology. 2008;48:322–335
  23. Enomoto N, Ikejima K, Bradford B, Rivera C, Kono H, Brenner DA, et al. Alcohol causes both tolerance and sensitization of rat Kupffer cells via mechanisms dependent on endotoxin. Gastroenterology. 1998;115:443–451
  24. 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
  25. Uesugi T, Froh M, Arteel GE, Bradford BU, Wheller MD, Gabele E, et al. Role of lipopolysaccharide-binding protein in early alcohol-induced liver injury in mice. J Immunol. 2002;168:2963–2969
  26. Yin M, Bradford BU, Wheeler MD, Uesugi T, Froh M, Goyert SM, et al. Reduced early alcohol-induced liver injury in CD14-deficient mice. J Immunol. 2001;166:4742–4747
  27. Romics L, Mandrekar P, Kodys K, Velayudham A, Drechsler Y, Dolganiuc A, et al. Increased lipopolysaccharide sensitivity in alcoholic fatty livers is independent of leptin deficiency and Toll-like receptor 4 (TLR4) or TLR2 mRNA expression. Alcohol Clin Exp Res. 2005;29:1018–1026
  28. Paik YH, Schwabe RF, Bataller R, Russo MP, Jobin C, Brenner DA. Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology. 2003;37:1043–1055
  29. Deaciuc IV, Spitzer JJ. Hepatic sinusoidal endothelial cell in alcoholemia and endotoxemia. Alcohol Clin Exp Res. 1996;20:607–614
  30. Nagy LE. Recent insights into the role of the innate immune system in the development of alcoholic liver disease. Exp Biol Med. 2003;228:882–890
  31. Gustot T, Lemmers A, Moreno C, Nagy N, Quertinmont E, Nicaise C, et al. Differential liver sensitization to Toll-like receptor pathways in mice with alcoholic fatty liver. Hepatology. 2006;43:989–1000
  32. Hritz I, Mandrekar P, Velayudham A, Catalano D, Dolganiuc A, Kurt-Jones E, et al. The critical role of Toll-like receptor 4 in alcoholic liver disease is independent of the common TLR adaptor, MyD88. Hepatology. 2008;48:1224–1231
  33. Fitzgerald KA, Rowe DC, Barnes BJ, Caffrey DR, Visintin A, Latz E, et al. LPS-TLR4 signaling to IRF-3 3/7 and NF-kappaB involves the Toll adaptors TRAM and TRIF. J Exp Med. 2003;198:1043–1055
  34. Kawai T, Takeuchi O, Fujita T, Inoue J, Mühlradt PF, Sato S, et al. Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J Immunol. 2001;167:5887–5894
  35. Takeda K, Akira S. TLR signaling pathways. Semin Immunol. 2004;16:3–9
  36. Yamamoto M, Sata S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, et al. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science. 2003;301:640–643
  37. Yamashina S, Wheeler MD, Rusyn I, Ikejima K, Sato N, Thurman RG. Tolerance and sensitization to endotoxin in Kupffer cells caused by acute ethanol involve interleukin-1 receptor-associated kinase. Biochem Biophys Res Commun. 2000;277:686–690
  38. Oak S, Mandrekar P, Catalano D, Kodys K, Szabo G. TLR2- and TLR4-mediated signals determine attenuation or augmentation of inflammation by acute alcohol in monocytes. J Immunol. 2006;176:7628–7635
  39. Pruett SB, Zheng Q, Fan R, Matthews K, Schwab C. Acute exposure to ethanol affects Toll-like receptor signaling and subsequent responses: an overview of recent studies. Alcohol. 2004;33:235–239
  40. Zhao XJ, Dong Q, Bindas J, Piganelli JD, Magill A, Reiser J, et al. TRIF and IRF-3 binding to the TNF promoter results in macrophage TNF dysregulation and steatosis induced by chronic ethanol. J Immunol. 2008;181:3049–3056
  41. Mandrekar P, Dolganiuc A, Bellerose G, Kodys K, Romics L, Nizamani R, et al. Acute alcohol inhibits the induction of nuclear regulatory factor kappa B activation through CD14/Toll-like receptor 4, interleukin-1, and tumor necrosis factor receptors: a common mechanism independent of inhibitory kappa B alpha degradation?. Alcohol Clin Exp Res. 2002;26:1609–1614
  42. Mandrekar P, Catalano D, White B, Szabo G. Moderate alcohol intake in humans attenuates monocyte inflammatory responses: inhibition of nuclear regulatory factor kappa B and induction of interleukin 10. Alcohol Clin Exp Res. 2006;30:135–139
  43. Kono H, Rusyn I, Yin M, Gäbele E, Yamashina S, Dikalova A, et al. NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease. J Clin Invest. 2000;106:867–872
  44. Thakur V, McMullen MR, Wang Q, Nagy LE. Enhanced LPS-stimulated ERK 1/2 activation and TNF alpha secretion by rat Kupffer cells after chronic ethanol feeding is mediated via increased production of reactive oxygen species (ROS) by NADPH oxidase. Hepatology. 2005;42:571A
  45. Park HS, Jung HY, Park EY, Kim J, Lee WJ, Bae YS. Cutting edge: direct interaction of TLR4 with NADPH 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
  46. Dasu MR, Devaraj S, Ling Z, Hwang DH, Jialal I. High glucose induces Toll-like receptor expression in human monocytes: mechanisms of activation. Diabetes. 2008;57:3090–3098
  47. Cao Q, Mak KM, Leiber CS. Dilinoleoylphosphatidylcholine decreases LPS-induced TNF-alpha generation in Kupffer cells of ethanol-fed rats: respective roles of MAPKs and NF-kappaB. Biochem Biophys Res Comm. 2002;294:849–853
  48. Ghosh S. Regulation of inducible gene expression by the transcription factor NF-kappaB. Immunol Res. 1999;19:183–189
  49. Wheeler MD, Yamashina S, Froh M, Rusyn I, Thurman RG. Adenoviral gene delivery can inactivate Kupffer cells: role of oxidants in NF-kappaB activation and cytokine production. J Leukoc Biol. 2001;69:622–630
  50. Nanji AA, Jokelainen K, Rahemtulla A, Miao L, Fogt F, Matsumoto H, et al. Activation of nuclear factor kappa B and cytokine imbalance in experimental alcoholic liver disease in the rat. Hepatology. 1999;30:934–943
  51. Hill DB, Barve S, Joshi-Barve S, McClain C. Increased monocyte nuclear factor-kappaB activation and tumor necrosis factor production in alcoholic hepatitis. J Lab Clin Med. 2000;135:387–395
  52. Mandrekar P, Catalano D, Szabo G. Inhibition of lipopolysaccharide-mediated NFkappaB activation by ethanol in human monocytes. Int Immunol. 1999;11:1781–1790
  53. Mandrekar P, Catalano D, Szabo G. Alcohol-induced regulation of nuclear regulatory factor-kappa beta in human monocytes. Alcohol Clin Exp Res. 1997;21:988–994
  54. Angel P, Karin M. The role of Jun, Fos and the AP-1 complex in cell proliferation and transformation. Biochem Biophys Acta. 1991;1072:129–157
  55. Shaulian E, Karin M. AP-1 in cell proliferation and survival. Oncogene. 2001;20:2390–2400
  56. Wheeler MD, Thurman RG. Upregulation of CD14 in liver due to acute ethanol involves oxidant-dependent AP-1 pathway. J Biol Chem. 2003;278:8345–8351
  57. Norkina O, Dolganiuc A, Shapiro T, Kodys K, Mandrekar P, Szabo G. Acute alcohol activates STAT3, AP-1, and Sp-1 transcription factors via the family of Src kinases to promote IL-10 production in human monocytes. J Leukoc Biol. 2007;82:752–762
  58. Casini A, Galli G, Salzano R, Ceni E, Franceschelli F, Rotella CM, et al. Acetaldehyde induces c-Fos and c-Jun proto-oncogenes in fat-storing cell cultures through protein kinase C activation. Alcohol Alcohol. 1994;29:303–314
  59. Kishore R, Hill JR, McMullen MR, Frenkel J, Nagy LE. ERK1/2 and Egr-1 contribute to increased TNF-alpha production in rat Kupffer cells after chronic ethanol feeding. Am J Physiol Gastrointest Liver Physiol. 2002;282:G6–G15
  60. Gashler A, Sukhatme VP. Early growth response protein 1 (Egr-1) prototype of a zinc-finger family of transcription factors. Prog Nucleic Acid Res Mol Biol. 1995;50:191–224
  61. Yan SF, Fujita T, Lu J, Okada K, Zou YS, Mackman N, et al. Egr-1, a master switch coordinating upregulation of divergent gene families underlying ischemic stress. Nat Med. 2000;6:1355–1361
  62. Pritchard MT, Nagy LE. Ethanol-induced liver injury: potential roles for egr-1. Alcohol Clin Exp Res. 2005;29:146S–150S
  63. McMullen MR, Pritchard MT, Wang Q, Millward CA, Croniger CM, Nagy LE. Early growth response-1 transcription factor is essential for ethanol-induced fatty liver injury in mice. Gastroenterology. 2005;128:2066–2076
  64. Darnell JE, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994;264:1415–1421
  65. Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW. Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene. 2002;285:1–24
  66. Kerr IM, Costa-Pereira AP, Lillemeier BF, Strobl B. Of JAKs, STATs, blind watchmakers, jeeps and trains. FEBS Lett. 2003;3:1–5
  67. Norkina O, Dolganiuc A, Catalano D, Kodys K, Mandrekar P, Syed A, et al. Acute alcohol intake induces SOCS1 and SOCS3 and inhibits cytokine-induced STAT1 and STAT3 signaling in human monocytes. Alcohol Clin Exp Res. 2008;32:1565–1573
  68. Chen J, Clemens DL, Cederbaum AI, Gao B. Ethanol inhibits the JAK-STAT signaling pathway in fresh isolated rat hepatocytes but not in cultured hepatocytes or HepG2 cells: evidence for a lack of involvement of ethanol metabolism. Clin Biochem. 2001;34:203–209
  69. Horiguchi N, Ishac EJ, Gao B. Liver regeneration is suppressed in alcoholic cirrhosis: correlation with decreased STAT3 activation. Alcohol. 2007;41:271–280
  70. Horiguchi N, Wang L, Mukhopadhyay P, Park O, Jeong WI, Lafdil F, et al. 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
  71. Yao J, Mackman N, Edgington TS, Fan ST. Lipopolysaccharide induction of the tumor necrosis factor-alpha promoter in human monocytic cells: regulation by Egr-1, c-jun and NF-kappaB transcription factors. J Biol Chem. 1997;272:17795–17801
  72. Shi L, Kishore R, McMullen MR, Frenkel J, Nagy LE. Chronic ethanol increases lipopolysaccharide stimulated Egr-1 expression in RAW 264.7 macrophages: contribution to enhanced tumor necrosis factor alpha production. J Biol Chem. 2002;277:14777–14785
  73. Kishore R, McMullen MR, Nagy LE. Stabilization of tumor necrosis factor alpha mRNA by chronic ethanol: role of A + U-rich elements and p38 mitogen-activated protein kinase signaling pathways. J Biol Chem. 2001;276:41930–41937
  74. Mahtani KR, Brook M, Dean JL, Sully G, Saklatvala J, Clark AR. Mitogen-activated protein kinase p38 controls the expression and posttranslational modification of tristetraprolin, a regulator of tumor necrosis factor alpha mRNA stability. Mol Cell Biol. 2001;21:6461–6469
  75. Drechsler Y, Dolganiuc A, Norkina O, Romics L, Li W, Kodys K, et al. Heme oxygenase-1 mediates the anti-inflammatory effects of acute alcohol on IL-10 induction involving p38 MAPK activation in monocytes. J Immunol. 2006;177:2592–2600
  76. Goral J, Kovacs EJ. In vivo ethanol exposure down-regulations TLR2-, TLR4-, and TLR9-mediated macrophage inflammatory response by limiting p38 and ERK1/2 activation. J Immunol. 2005;174:456–463
  77. Song Z, Zhou Z, Uriarte S, Wang S, Kang YJ, Chen T, et al. S-adenosylhomocysteine sensitizes to TNF-alpha hepatotoxicity in mice and liver cells: a possible etiological factor in alcoholic liver disease. Hepatology. 2004;40:989–997
  78. McClain C, Hill D, Schmidt J, Diehl AM. Cytokines and alcoholic liver disease. Semin Liver Dis. 1993;13:170–182
  79. Honchel R, Ray M, Marsano L, Cohen D, Lee E, Shedlofsky S, et al. Tumor necrosis factor in alcohol-enhanced endotoxin liver injury. Alcohol Clin Exp Res. 1992;16:665–669
  80. Thurman RG. Mechanisms of hepatic toxicity. III. Alcoholic liver injury involves activation of Kupffer cells by endotoxin. Am J Physiol. 1998;275:G605–G611
  81. Tilg H, Jalan R, Kaser A, Davies NA, Offner FA, Hodges SI, et al. Anti-tumor necrosis factor-alpha monoclonal antibody therapy in severe alcoholic hepatitis. J Hepatol. 2003;38:419–425
  82. Imuro Y, Gallucci RM, Luster MI, Kono H, Thurman RG. Antibodies to tumor necrosis factor alpha attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat. Hepatology. 1997;26:1530–1537
  83. Yin M, Wheeler MD, Kono H, Bradford BU, Gallucci RM, Luster MI, et al. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology. 1999;117:942–952
  84. McClain CJ, Barve S, Barve S, Deaciuc I, Hill DB. Tumor necrosis factor and alcoholic liver disease. Alcohol Clin Exp Res. 1998;22:248S–252S
  85. Olleros ML, Martin ML, Vesin D, Fotio AL, Santiago-Rober ML, Rubbia-Brandt L, et al. Fat diet and alcohol-induced steatohepatitis after LPS challenge in mice: role of bioactive TNF and Th1 type cytokines. Cytokine. 2008;44:118–125
  86. Schmidt-Weber CB, Blaser K. Regulation and role of transforming growth factor-beta in immune tolerance induction and inflammation. Curr Opin Immunol. 2004;16:709–716
  87. Asadullah K, Sterry W, Volk HD. Interleukin-10 therapy – review of a new approach. Pharmacol Rev. 2003;55:241–269
  88. Liew FY, Xu D, Brint EK, Oneill LA. Negative regulation of Toll-like receptor-mediated immune responses. Nat Rev Immunol. 2005;5:446–458
  89. Hill DB, D’Souza NB, Lee EY, Burikhanov R, Deaciuc IV, deVilliers WJ. A role for interleukin-10 in alcohol-induced liver sensitization to bacterial lipopolysaccharide. Alcohol Clin Exp Res. 2002;26:74–82
  90. Thakur V, Prtichard MT, McMullen MR, Nagy LE. Adiponectin normalizes LPS-stimulated TNF-alpha production by rat Kupffer cells after chronic ethanol feeding. Am J Physiol Gastrointest Liver Physiol. 2006;290:G998–G1007
  91. Huang H, Park PH, McMullen MR, Nagy LE. Mechanisms for the anti-inflammatory effects of adiponectin in macrophages. J Gastroenterol Hepatol. 2008;23:S850–S853
  92. Mandrekar P, Catalano D, Girouard L, Szabo G. Human monocyte IL-10 production is increased by acute ethanol treatment. Cytokine. 1996;8:567–577
  93. 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

 The underlying research reported in the study was funded by the NIH Institutes of Health, NIH AA017357 and AA015283 conference grant. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding from industry or conflict of interest with respect to this manuscript.

PII: S0168-8278(09)00168-8

doi: 10.1016/j.jhep.2009.03.007

Journal of Hepatology
Volume 50, Issue 6 , Pages 1258-1266 , June 2009