Mechanisms of the inflammatory reaction implicated in alcoholic hepatitis: 2011 update

Clinics and Research in Hepatology and Gastroenterology

Volumn 35, Issue 6-7, 2011, Pages 465-474

  Voican, Cosmin Sebastian ^b,d   Perlemuter, Gabriel ^a,b,c   Naveau, Sylvie ^a,b,c  

^a HÔPITAL ANTOINE BÉCLÈRE   (France)

^b Universite Paris Sud   (France)

^c UNIVERSITÉ PARIS SACLAY   (France)

^d Universitatea de Medicina si Farmacie Craiova   (Romania)

Author keywords

[No Author keywords available]

Indexed keywords

ALCOHOL; CYTOCHROME P450 2E1; ENDOTOXIN; GADOLINIUM CHLORIDE; HEPCIDIN; HISTONE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 1BETA; INTERLEUKIN 22; INTERLEUKIN 6; INTERLEUKIN 8; IRON; LEUCINE ZIPPER PROTEIN; LIPOPOLYSACCHARIDE; LIPOPOLYSACCHARIDE BINDING PROTEIN; MONOCYTE CHEMOTACTIC PROTEIN 1; OSTEOPONTIN; PATTERN RECOGNITION RECEPTOR; PREDNISOLONE; PROHEPCIDIN; RANTES; REACTIVE OXYGEN METABOLITE; TRANSCRIPTION FACTOR AP 1; TUMOR NECROSIS FACTOR ALPHA; TUMOR NECROSIS FACTOR ALPHA ANTIBODY; TUMOR NECROSIS FACTOR ALPHA INHIBITOR;

ALCOHOL CONSUMPTION; ALCOHOL LIVER DISEASE; ANTIINFLAMMATORY ACTIVITY; ARTICLE; BACTERIAL COLONIZATION; BACTEROIDETES; CELL ACTIVATION; CELL ADHESION; CORTICOSTEROID THERAPY; CYTOKINE PRODUCTION; DEACETYLATION; DNA BINDING; DNA DAMAGE; GENE EXPRESSION; HISTONE ACETYLATION; HUMAN; INNATE IMMUNITY; INTESTINE FLORA; IRON ABSORPTION; IRON OVERLOAD; KUPFFER CELL; LACTOBACILLUS; LEUKOCYTE ACTIVATION; LIVER HISTOLOGY; LYMPHOCYTIC INFILTRATION; MONOTHERAPY; NEUTROPHIL CHEMOTAXIS; NONHUMAN; OXIDATIVE STRESS; OXYGEN TRANSPORT; PATHOGENESIS; PATHOPHYSIOLOGY; SIGNAL TRANSDUCTION; TIGHT JUNCTION; TRANSACTIVATION; ZINC DEFICIENCY;

EID: 80052313471     PISSN: 22107401     EISSN: 2210741X     Source Type: Journal    
DOI: 10.1016/j.clinre.2011.01.017     Document Type: Review

References (106)

1. Rehm J, Mathers C, Popova S, Thavorncharoensap M, Teerawattananon Y, Patra J. Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet 2009;373:2223-33.
2. Naveau S. Current trend: alcoholic liver diseases. Gastroenterol Clin Biol 2006;30:550-3.
3. Lefkowitch JH. Morphology of alcoholic liver disease. Clin Liver Dis 2005;9:37-53.
4. Chedid A, Arain S, Snyder A, Mathurin P, Capron F, Naveau S. The immunology of fibrogenesis in alcoholic liver disease. Arch Pathol Lab Med 2004;128:1230-8.
5. Colombat M, Charlotte F, Ratziu V, Poynard T. Portal lymphocytic infiltrate in alcoholic liver disease. Hum Pathol 2002;33:1170-4.
6. Adachi Y, Bradford BU, Gao W, Bojes HK, Thurman RG. Inactivation of Kupffer cells prevents early alcohol-induced liver injury. Hepatology 1994;20:453-60.
7. Rao R. Endotoxemia and gut barrier dysfunction in alcoholic liver disease. Hepatology 2009;50:638-44.
8. Adachi Y, Moore LE, Bradford BU, Gao W, Thurman RG. Antibiotics prevent liver injury in rats following long-term exposure to ethanol. Gastroenterology 1995;108:218-24.
9. Nanji AA, Khettry U, Sadrzadeh SM. Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver (disease). Proc Soc Exp Biol Med 1994;205:243-7.
10. Parlesak A, Schäfer C, Schütz T, Bode JC, Bode C. Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease. J Hepatol 2000;32:742-7.
11. Tamai H, Kato S, Horie Y, Ohki E, Yokoyama H, Ishii H. Effect of acute ethanol administration on the intestinal absorption of endotoxin in rats. Alcohol Clin Exp Res 2000;24:390-4.
12. Nanji AA, Khettry U, Sadrzadeh SM, Yamanaka T. Severity of liver injury in experimental alcoholic liver disease. Correlation with plasma endotoxin, prostaglandin E2, leukotriene B4, and thromboxane B2. Am J Pathol 1993;142:367-73.
13. Mathurin P, Deng QG, Keshavarzian A, Choudhary S, Holmes EW, Tsukamoto H. Exacerbation of alcoholic liver injury by enteral endotoxin in rats. Hepatology 2000;32:1008-17.
14. Keshavarzian A, Farhadi A, Forsyth CB, et al. Evidence that chronic alcohol exposure promotes intestinal oxidative stress, intestinal hyperpermeability and endotoxemia prior to development of alcoholic steatohepatitis in rats. J Hepatol 2009;50:538-47.
15. Parlesak A, Schäfer C, Schütz T, Bode JC, Bode C. Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-inducedliver disease. J Hepatol 2000;32:742-7.
16. Ma TY, Nguyen D, Bui V, Nguyen H, Hoa N. Ethanol modulation of intestinal epithelial tight junction barrier. Am J Physiol 1999;276:G965-74.
17. Jokelainen K, Roine RP, Väänänen H, Färkkilä M, Salaspuro M. In vitro acetaldehyde formation by human colonic bacteria. Gut 1994;35:1271-4.
18. Koivisto T, Salaspuro M. Aldehyde dehydrogenases of the rat colon: comparison with other tissues of the alimentary tract and the liver. Alcohol Clin Exp Res 1996;20:551-5.
19. Basuroy S, Sheth P, Mansbach CM, Rao RK. Acetaldehyde disrupts tight junctions and adherens junctions in human colonic mucosa: protection by EGF and L-glutamine. Am J Physiol Gastrointest Liver Physiol 2005;289:G367-75.
20. Tang Y, Forsyth CB, Farhadi A, et al. Nitric oxide-mediated intestinal injury is required for alcohol-induced gut leakiness and liver damage. Alcohol Clin Exp Res 2009;33:1220-30.
21. ZhongW, McClain CJ, Cave M, Kang YJ, Zhou Z. The role of zinc deficiency in alcohol-induced intestinal barrier dysfunction. Am J Physiol Gastrointest Liver Physiol 2010;298:G625-33.
22. Banan A, Fields JZ, Decker H, Zhang Y, Keshavarzian A. Nitric oxide and its metabolites mediate ethanol-induced microtubule disruption and intestinal barrier dysfunction. J Pharmacol Exp Ther 2000;294:997-1008.
23. Sekirov I, Russell SL, Antunes LC, Finlay BB. Gut microbiota in health and disease. Physiol Rev 2010;90:859-904.
24. Yan AW, Fouts ED, Brandl J, et al. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology 2010, doi:10.1002/hep.24018.
25. Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 1990;249:1431-3.
26. Chow JC, Young DW, Golenbock DT, Christ WJ, Gusovsky F. Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J Biol Chem 1999;274:10689-92.
27. Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998;282:2085-8.
28. Shimazu R, Akashi S, Ogata H, et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on toll-like receptor 4. J Exp Med 1999;189:1777-82.
29. Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature 2009;458:1191-5.
30. Nanji AA, Jokelainen K, Rahemtulla A, et al. Activation of nuclear factor kappa B and cytokine imbalance in experimental alcoholic liver disease in the rat. Hepatology 1999;30:934-43.
31. Takeda K, Akira S. TLR signaling pathways. Semin Immunol 2004;16:3-9.
32. Hoshino K, Takeuchi O, Kawai T, et al. Cutting edge: tolllike receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 1999;162:3749-52.
33. Uesugi T, Froh M, Arteel GE, et al. Role of lipopolysaccharidebinding protein in early alcohol-induced liver injury in mice. J Immunol 2002;168:2963-9.
34. Yin M, Bradford BU, Wheeler MD, et al. Reduced early alcoholinduced liver injury in CD14-deficient mice. J Immunol 2001;166:4737-42.
35. Gustot T, Lemmers A, Moreno C, et al. Differential liver sensitization to toll-like receptor pathways in mice with alcoholic fatty liver. Hepatology 2006;43:989-1000.
36. Roychowdhury S, McMullen MR, Pritchard MT, et al. An early complement-dependent andTLR-4-independent phase in the pathogenesis of ethanol-induced liver injury in mice. Hepatology 2009;49:1326-34.
37. Cohen JI, Roychowdhury S, McMullen MR, Stavitsky AB, Nagy LE. Complement and alcoholic liver disease: role of C1q in the pathogenesis of ethanol-induced liver injury in mice. Gastroenterology 2010;139:664-74.
38. Bell H, Skinningsrud A, Raknerud N, Try K. Serum ferritin and transferrin saturation in patients with chronic alcoholic and non-alcoholic liver diseases. J Intern Med 1994;236:315-22.
39. Ioannou GN, Dominitz JA, Weiss NS, Heagerty PJ, Kowdley KV. The effect of alcohol consumption on the prevalence of iron overload, iron deficiency, and iron deficiency anemia. Gastroenterology 2004;126:1293-301.
40. Valerio Jr LG, Parks T, Petersen DR. Alcohol mediates increases in hepatic and serum nonheme iron stores in a rat model for alcohol-induced liver injury. Alcohol Clin Exp Res 1996;20:1352-61.
41. Bridle KR, Cheung TK, Murphy L, et al. Hepcidin is downregulated in alcoholic liver injury: implications for the pathogenesis of alcoholic liver disease. Alcohol Clin Exp Res 2006;30:106-12.
42. Harrison-Findik DD, Schafer D, Klein E, et al. Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression. J Biol Chem 2006;281: 22974-82.
43. Ohtake T, Saito H, Hosoki Y, et al. Hepcidin is down-regulated in alcohol loading. Alcohol Clin Exp Res 2007;31:S2-8.
44. Tsukamoto H, Lin M, Ohata M, Giulivi C, French SW, Brittenham G. Iron primes hepatic macrophages for NF-kB activation in alcoholic liver injury. AmJ Physiol Gastrointest Liver Physiol 1999;277:G1240-50.
45. She H, Xiong S, Lin M, Zandi E, Giulivi C, Tsukamoto H. Iron activates NF-kB in Kupffer cells. Am J Physiol Gastrointest Liver Physiol 2002;283:G719-26.
46. Shi X, Dong Z, Huang C, et al. The role of hydroxyl radical as a messenger in the activation of nuclear transcription factor NF-kappaB. Mol Cell Biochem 1999;194:63-70.
47. Meagher EA, Barry OP, Burke A, et al. Alcohol-induced generation of lipid peroxidation products in humans. J Clin Invest 1999;104:805-13.
48. Naveau S, Abella A, Raynard B, et al. Tumor necrosis factor soluble receptor p55 and lipid peroxidation in patients with acute alcoholic hepatitis. Am J Gastroenterol 2001;96:3361-7.
49. Kono H, Rusyn I, Yin M, et al. NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease. J Clin Invest 2000;106:867-72.
50. Knecht KT, Adachi Y, Bradford BU, et al. Free radical adducts in the bile of rats treated chronically with intragastric alcohol: inhibition by destruction of Kupffer cells. Mol Pharmacol 1995;47:1028-34.
51. Lu Y, Zhuge J, Wang X, Bai J, Cederbaum AI. Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice. Hepatology 2008;47:1483-94.
52. Cao Q, Mak KM, Lieber CS. Cytochrome P4502E1 primes macrophages to increase TNF-αproduction in response to lipopolysaccharide. Am J Physiol Gastrointest Liver Physiol 2005;289:G95-107.
53. Rolla R, Vay D, Mottaran E, et al. Detection of circulating antibodies against malondialdehyde-acetaldehyde adducts in patients with alcohol-induced liver disease. Hepatology 2000;31:878-84.
54. Stewart SF, Vidali M, Day CP, Albano E, Jones DE. Oxidative stress as a trigger for cellular immune responses in patients with alcoholic liver disease. Hepatology 2004;39:197-203.
55. Vidali M, Hietala J, Occhino G, et al. Immune responses against oxidative stress-derived antigens are associated with increased circulating tumor necrosis factor-α in heavy drinkers. Free Radic Biol Med 2008;45:306-11.
56. Lee DY, Hayes JJ, Pruss D, Wolffe AP. A positive role for histone acetylation in transcription factor access to DNA. Cell 1993;72:73-84.
57. Grunstein M. Histone acetylation in chromatin structure and transcription. Nature 1997;389:349-52.
58. Kendrick SFW, O'Boyle G, Mann J, et al. Acetate, the key modulator of inflammatory responses in acute alcoholic hepatitis. Hepatology 2010;51:1988-97.
59. Yin M, Wheeler MD, Kono H, et al. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology 1999;117:942-52.
60. Naveau S, Emilie D, Balian A, et al. Plasma levels of soluble tumor necrosis factor receptors p55 and p75 in patients with alcoholic liver disease of increasing severity. J Hepatol 1998;28:778-84.
61. Colmenero J, Bataller R, Sancho-Bru P, et al. Hepatic expression of candidate genes in patients with alcoholic hepatitis: correlation with disease severity. Gastroenterology 2007;132:687-97.
62. Spahr L, Giostra E, Frossard JL, Bresson-Hadni S, Rubbia-Brandt L, Hadengue A. Soluble TNF-R1, but not tumor necrosis factor alpha, predicts the 3-month mortality in patients with alcoholic hepatitis. J Hepatol 2004;41:229-34.
63. Iimuro Y, Gallucci RM, Luster MI, Kono H, Thurman RG. Antibodies to tumor necrosis factor alfa attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat. Hepatology 1997;26:1530-7.
64. Naveau S. Mechanisms of the inflammatory reaction implicated in acute experimental alcoholic hepatitis. Gastroenterol Clin Biol 2001;25:137-43.
65. Boetticher NC, Peine CJ, Kwo P, et al. A randomized, doubleblinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis. Gastroenterology 2008;135:1953-60.
66. Naveau S, Chollet-Martin S, Dharancy S, et al. A doubleblind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis. Hepatology 2004;39:1390-7.
67. Naveau S. Traitement de l'hépatite alcoolique aiguë sévère par infliximab. Gastroenterol Clin Biol 2004;28:619-24.
68. Jura J, Wegrzyn P, Korostynski M, et al. Identification of interleukin-1 and interleukin-6-responsive genes in human monocyte-derived macrophages using microarrays. Biochim Biophys Acta 2008;1779:383-9.
69. Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1beta and 6 but not transforming growth factorbeta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 2007;8:942-9.
70. Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 2007;25:821-52.
71. Lemmers A, Moreno C, Gustot T, et al. The interleukin-17 pathway is involved in human alcoholic liver disease. Hepatology 2009;49:646-57.
72. Takahashi N, Vanlaere I, de Rycke R, et al. IL-17 produced by Paneth cells drives TNF-induced shock. J Exp Med 2008;205:1755-61.
73. Lafdil F, Miller AM, Ki SH, Gao B. Th17 cells and their associated cytokines in liver diseases. Cell Mol Immunol 2010;7:250-4.
74. Ki SH, Park O, Zheng M, et al. Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3. Hepatology 2010;52:1291-300.
75. Sheron N, Bird G, Goka J, Alexander G, Williams R. Elevated plasma interleukin-6 and increased severity and mortality in alcoholic hepatitis. Clin exp Immunol 1991;84:449-53.
76. Hong F, Kim WH, Tian Z, et al. Elevated interleukin-6 during ethanol consumption acts as a potential endogenous protective cytokine against ethanol-induced apoptosis in the liver: involvement of induction of Bcl-2 and Bcl-xL proteins. Oncogene 2002;21:32-43.
77. Zhang X, Tachibana S, Wang H, et al. Interleukin-6 is an important mediator for mitochondrial DNA repair after alcoholic liver injury in mice. Hepatology 2010;52:2137-47.
78. Rabe B, Chalaris A, May U, et al. Transgenic blockade of interleukin 6 transsignaling abrogates inflammation. Blood 2008;111:1021-8.
79. Sabat R, Grütz G, Warszawska K, Kirsch S, Witte E, Wolk K, et al. Biology of interleukin-10. Cytokine Growth Factor Rev 2010;21:331-44.
80. Horiguchi N, Wang L, Mukhopadhyay P, et al. Cell typedependent pro- and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury. Gastroenterology 2008;134:1148-58.
81. Hill DB, D'Souza NB, Lee EY, Burikhanov R, Deaciuc IV, de Villiers WJ. A role for interleukin-10 in alcohol-induced liver sensitization to bacterial lipopolysaccharide. Alcohol Clin Exp Res 2002;26:74-82.
82. Naveau S, Balian A, Capron F, et al. Balance between pro and anti-inflammatory cytokines in patients with acute alcoholic hepatitis. Gastroenterol Clin Biol 2005;29:269-74.
83. Ayroldi E, Riccardi C. Glucocorticoid-induced leucine zipper (GILZ): a new important mediator of glucocorticoid action. FASEB J 2009;23:3649-58.
84. Berrebi D, Bruscoli S, Cohen N, et al. Synthesis of glucocorticoid-induced leucine zipper (GILZ) by macrophages: an anti-inflammatory and immunosuppressive mechanism shared by glucocorticoids and IL-10. Blood 2003;101:729-38.
85. Hamdi H, Bigorgne A, Naveau S, et al. Glucocorticoid-induced leucine zipper: a key protein in the sensitization of monocytes to lipopolysaccharide in alcoholic hepatitis. Hepatology 2007;46:1986-92.
86. Thornton AJ, Strieter RM, Lindley I, Baggiolini M, Kunkel SL. Cytokine-induced gene expression of a neutrophil chemotactic factor/IL-8 in human hepatocytes. J Immunol 1990;144:2609-13.
87. 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;37:1043-55.
88. Paik YH, Lee KS, Lee HJ, et al. Hepatic stellate cells primed with cytokines upregulate inflammation in response to peptidoglycan or lipoteichoic acid. Lab Invest 2006;86:676-86.
89. Montecucco F, Steffens S, Burger F, et al. Tumor necrosis factor-alpha (TNF-α) induces integrin CD11b/CD18 (Mac-1) up-regulation and migration to the CC chemokine CCL3 (MIP-1α) on human neutrophils through defined signalling pathways. Cell Signal 2008;20:557-68.
90. Mookerjee RP, Stadlbauer V, Lidder S, et al. Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome. Hepatology 2007;46:831-40.
91. Fan J, Malik AB. Toll-like receptor-4 (TLR4) signaling augments chemokine-induced neutrophil migration by modulating cell surface expression of chemokine receptors. Nat Med 2003;9:315-21.
92. Woodfin A, Voisin MB, Nourshargh S. Recent developments and complexities in neutrophil transmigration. Curr Opin Hematol 2010;17:9-17.
93. Kono H, Uesugi T, Froh M, Rusyn I, Bradford BU, Thurman RG. ICAM-1 is involved in the mechanism of alcohol-induced liver injury: studies with knockout mice. Am J Physiol Gastrointest Liver Physiol 2001;280:G1289-95.
94. Ramaiah SK, Rittling S. Pathophysiological role of osteopontin in hepatic inflammation, toxicity, and cancer. Toxicol Sci 2008;103:4-13.
95. Apte UM, Banerjee A, McRee R, Wellberg E, Ramaiah SK. Role of osteopontin in hepatic neutrophil infiltration during alcoholic steatohepatitis. Toxicol Appl Pharmacol 2005;207:25-38.
96. Banerjee A, Apte UM, Smith R, Ramaiah SK. Higher neutrophil infiltration mediated by osteopontin is a likely contributing factor to the increased susceptibility of females to alcoholic liver disease. J Pathol 2006;208:473-85.
97. Banerjee A, Lee JH, Ramaiah SK. Interaction of osteopontin with neutrophil α4β1 and α9β1 integrins in a rodent model of alcoholic liver disease. Toxicol Appl Pharmacol 2008;233:238-46.
98. Jaeschke H, Hasegawa T. Role of neutrophils in acute inflammatory liver injury. Liver Int 2006;26:912-9.
99. 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;126:1387-99.
100. 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;134:248-58.
101. Gurung P, Young BM, Coleman RA, et al. Chronic ethanol induces inhibition of antigen-specific CD8+ but not CD4+ immunodominant T cell responses following Listeria monocytogenes inoculation. J Leukoc Biol 2009;85:34-43.
102. Cook RT, Zhu X, Coleman RA, et al. T-cell activation after chronic ethanol ingestion in mice. Alcohol 2004;33: 175-81.
103. Hirano F, Komura K, Fukawa E, Makino I. Tumor necrosis factor alpha (TNF-alpha)-induced RANTES chemokine expression via activation of NF-kappaB and p38 MAP kinase: roles of TNF-alpha in alcoholic liver diseases. J Hepatol 2003;38: 483-9.
104. Pelletier M, Maggi L, Micheletti A, et al. Evidence for a cross-talk between human neutrophils and Th17 cells. Blood 2010;115:335-43.
105. 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;287:471-9.
106. 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;130:435-52.