IFN-γ deficiency attenuates hepatic inflammation and fibrosis in a steatohepatitis model induced by a methionine- and choline-deficient high-fat diet

American Journal of Physiology - Gastrointestinal and Liver Physiology

Volumn 305, Issue 12, 2013, Pages

  Luo, Xiao Yu ^a,b,f   Takahara, Terumi ^b   Kawai, Kengo ^b   Fujino, Masayuki ^a,c   Sugiyama, Toshiro ^b   Tsuneyama, Koichi ^b   Tsukada, Kazuhiro ^b   Nakae, Susumu ^d,e   Zhong, Liang ^f   Li, Xiao Kang ^a  

^a NATIONAL RESEARCH INSTITUTE FOR CHILD HEALTH AND DEVELOPMENT   (Japan)

^b UNIVERSITY OF TOYAMA   (Japan)

^c NATIONAL INSTITUTE OF INFECTIOUS DISEASES   (Japan)

^d UNIVERSITY OF TOKYO   (Japan)

^e JAPAN SCIENCE AND TECHNOLOGY AGENCY   (Japan)

^f FUDAN UNIVERSITY   (China)

Author keywords

Hepatic stellate cell; Interferon ; Macrophage

Indexed keywords

ALANINE AMINOTRANSFERASE; ALPHA SMOOTH MUSCLE ACTIN; ASPARTATE AMINOTRANSFERASE; CHOLESTEROL; COLLAGEN TYPE 1; GAMMA INTERFERON; GELATINASE A; INDUCIBLE NITRIC OXIDE SYNTHASE; INTERLEUKIN 4; METHIONINE; OSTEOPONTIN; TISSUE INHIBITOR OF METALLOPROTEINASE 1; TRANSFORMING GROWTH FACTOR BETA; TRIACYLGLYCEROL; TUMOR NECROSIS FACTOR ALPHA;

ALANINE AMINOTRANSFERASE BLOOD LEVEL; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; CELL INFILTRATION; CHOLESTEROL BLOOD LEVEL; CONTROLLED STUDY; CYTOKINE PRODUCTION; DISEASE COURSE; FIBROSIS; GENE EXPRESSION; HEPATITIS; IMMUNE DEFICIENCY; INFLAMMATION; INTERFERON GAMMA DEFICIENCY; KUPFFER CELL; LIPID DIET; LIVER FIBROSIS; LIVER HISTOLOGY; MACROPHAGE; MOUSE; MYOFIBROBLAST; NONHUMAN; PRIORITY JOURNAL; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; TRIACYLGLYCEROL BLOOD LEVEL; VITAMIN DEFICIENCY; WEIGHT REDUCTION; WILD TYPE;

HEPATIC STELLATE CELL; INTERFERON-Γ; MACROPHAGE;

ANIMALS; CELL LINE; CHOLINE DEFICIENCY; DIET, HIGH-FAT; DISEASE MODELS, ANIMAL; FATTY LIVER; GENE EXPRESSION PROFILING; HEPATIC STELLATE CELLS; INFLAMMATION; INTERFERON-GAMMA; KUPFFER CELLS; LIVER; LIVER CIRRHOSIS; MACROPHAGES; MALE; METHIONINE; MICE; MICE, INBRED C57BL; NITRIC OXIDE SYNTHASE TYPE II; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR-ALPHA;

EID: 84890328256     PISSN: 01931857     EISSN: 15221547     Source Type: Journal    
DOI: 10.1152/ajpgi.00193.2013     Document Type: Article

References (81)

1. Adler M, Taylor S, Okebugwu K, Yee H, Fielding C, Fielding G, Poles M. Intrahepatic natural killer T cell populations are increased in human hepatic steatosis. World J Gastroenterol 17: 1725-1731, 2011.
2. Alkhouri N, Morris-Stiff G, Campbell C, Lopez R, Tamimi TA, Yerian L, Zein NN, Feldstein AE. Neutrophil to lymphocyte ratio: a new marker for predicting steatohepatitis and fibrosis in patients with nonalcoholic fatty liver disease. Liver Int 32: 297-302, 2012.
3. Bahcecioglu IH, Koca SS, Poyrazoglu OK, Yalniz M, Ozercan IH, Ustundag B, Sahin K, Dagli AF, Isik A. Hepatoprotective effect of infliximab, an anti-TNF-alpha agent, on carbon tetrachloride-induced hepatic fibrosis. Inflammation 31: 215-221, 2008.
4. Bahcecioglu IH, Yalniz M, Ataseven H, Ilhan N, Ozercan IH, Seckin D, Sahin K. Levels of serum hyaluronic acid, TNF-alpha and IL-8 in patients with nonalcoholic steatohepatitis. Hepato-Gastroenterology 52: 1549-1553, 2005.
5. Bansal R, Prakash J, Post E, Beljaars L, Schuppan D, Poelstra K. Novel engineered targeted interferon-gamma blocks hepatic fibrogenesis in mice. Hepatology 54: 586-596, 2011.
6. 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 23: 1189-1199, 1996.
7. Bertola A, Deveaux V, Bonnafous S, Rousseau D, Anty R, Wakkach A, Dahman M, Tordjman J, Clement K, McQuaid SE, Frayn KN, Huet PM, Gugenheim J, Lotersztajn S, Le Marchand-Brustel Y, Tran A, Gual P. Elevated expression of osteopontin may be related to adipose tissue macrophage accumulation and liver steatosis in morbid obesity. Diabetes 58: 125-133, 2009.
8. Block ET, Cronstein BN. Interferon-gamma inhibits adenosine A2A receptor function in hepatic stellate cells by STAT1-mediated repression of adenylyl cyclase. Int J Interferon Cytokine Mediator Res 2010: 113-126, 2010.
9. Border WA, Noble NA. Transforming growth-factor-beta in tissue fibrosis. N Engl J Med 331: 1286-1292, 1994.
10. Cao Q, Batey R, Pang G, Russell A, Clancy R. IL-6, IFN-gamma and TNF-alpha production by liver-associated T cells and acute liver injury in rats administered concanavalin A. Immunol Cell Biol 76: 542-549, 1998.
11. Chikano S, Sawada K, Shimoyama T, Kashiwamura SI, Sugihara A, Sekikawa K, Terada N, Nakanishi K, Okamura H. IL-18 and IL-12 induce intestinal inflammation and fatty liver in mice in an IFN-gamma dependent manner. Gut 47: 779-786, 2000.
12. Day CP. From fat to inflammation. Gastroenterology 130: 207-210, 2006.
13. Diehl AM. Nonalcoholic steatosis and steatohepatitis. IV. Nonalcoholic fatty liver disease abnormalities in macrophage function and cytokines. Am J Physiol Gastrointest Liver Physiol 282: G1-G5, 2002.
14. Dixon LJ, Berk M, Thapaliya S, Papouchado BG, Feldstein AE. Caspase-1-mediated regulation of fibrogenesis in diet-induced steatohepatitis. Lab Invest 92: 713-723, 2012.
15. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 43: S99-S112, 2006.
16. Ferreyra Solari NE, Inzaugarat ME, Baz P, De Matteo E, Lezama C, Galoppo M, Galoppo C, Chernavsky AC. The role of innate cells is coupled to a Th1-polarized immune response in pediatric nonalcoholic steatohepatitis. J Clin Immunol 32: 611-621, 2012.
17. Fourcot A, Couchie D, Chobert MN, Zafrani ES, Mavier P, Laperche Y, Brouillet A. Gas6 deficiency prevents liver inflammation, steatohepatitis, and fibrosis in mice. Am J Physiol Gastrointest Liver Physiol 300: G1043-G1053, 2011.
18. Frankova D, Zidek Z. IFN-gamma-induced TNF-alpha is a prerequisite for in vitro production of nitric oxide generated in murine peritoneal macrophages by IFN-gamma. Eur J Immunol 28: 838-843, 1998.
19. Friedman SL, Flier JS, Epstein F, Glickman R, Scheele G. Seminars in medicine of the Beth-Israel-Hospital, Boston-the cellular basis of hepaticfibrosis- mechanisms and treatment strategies. N Engl J Med 328: 1828-1835, 1993.
20. Frucht DM, Fukao T, Bogdan C, Schindler H, O'Shea JJ, Koyasu S. IFN-gamma production by antigen-presenting cells: mechanisms emerge. Trends Immunol 22: 556-560, 2001.
21. Gabele E, Froh M, Arteel GE, Uesugi T, Hellerbrand C, Scholmerich J, Brenner DA, Thurman RG, Rippe RA. TNF alpha is required for cholestasis-induced liver fibrosis in the mouse. Biochem Biophys Res Commun 378: 348-353, 2009.
22. Gao B, Jeong WI, Tian Z. Liver: An organ with predominant innate immunity. Hepatology 47: 729-736, 2008.
23. Gonzalez-Reimers E, Castellano-Higuera A, Aleman-Valls R, Alvarez- Arguelles H, de la Vega-Prieto MJ, Abreu-Gonzalez P, Lopez-Prieto J, Santolaria-Fernandez F, Valladares-Parrilla F. Relation between body fat and liver fat accumulation and cytokine pattern in non-alcoholic patients with chronic HCV infection. Ann Nutr Metab 55: 351-357, 2009.
24. Guo H, Cai CQ, Schroeder RA, Kuo PC. Osteopontin is a negative feedback regulator of nitric oxide synthesis in murine macrophages. J Immunol 166: 1079-1086, 2001.
25. Horras CJ, Lamb CL, Mitchell KA. Regulation of hepatocyte fate by interferon-gamma. Cytokine Growth Factor Rev 22: 35-43, 2011.
26. Huang W, Metlakunta A, Dedousis N, Zhang PL, Sipula I, Dube JJ, Scott DK, O'Doherty RM. Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes 59: 347-357, 2010.
27. Inagaki Y, Nemoto T, Kushida M, Sheng Y, Higashi K, Ikeda K, Kawada N, Shirasaki F, Takehara K, Sugiyama K, Fujii M, Yamauchi H, Nakao A, de Crombrugghe B, Watanabe T, Okazaki I. Interferon alfa down-regulates collagen gene transcription and suppresses experimental hepatic fibrosis in mice. Hepatology 38: 890-899, 2003.
28. Inoue A, Yanagisawa M, Takuwa Y, Mitsui Y, Kobayashi M, Masaki T. The human preproendothelin-1 gene. Complete nucleotide sequence and regulation of expression. J Biol Chem 264: 14954-14959, 1989.
29. Ishida Y, Kondo T, Ohshima T, Fujiwara H, Iwakura Y, Mukaida N. A pivotal involvement of IFN-gamma in the pathogenesis of acetaminophen- induced acute liver injury. FASEB J 16: 1227-1236, 2002.
30. Ishikawa S, Ikejima K, Yamagata H, Aoyama T, Kon K, Arai K, Takeda K, Watanabe S. CD1d-restricted natural killer T cells contribute to hepatic inflammation and fibrogenesis in mice. J Hepatol 54: 1195-1204, 2011.
31. Jaruga B, Hong F, Kim WH, Gao B. IFN-gamma/STAT1 acts as a proinflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: a critical role of IRF-1. Am J Physiol Gastrointest Liver Physiol 287: G1044-G1052, 2004.
32. Kang YH, Seigel B, Bengsch B, Fleming VM, Billerbeck E, Simmons R, Walker L, Willberg CB, Barnes EJ, Bhagwanani A, Oo YH, Blum HE, Adams DH, Thimme R, Klenerman P. CD161(+)CD4(+) T cells are enriched in the liver during chronic hepatitis and associated with co-secretion of IL-22 and IFN-gamma (Abstract). Frontiers Immunol 3: 346, 2012.
33. Kanzler S, Lohse AW, Keil A, Henninger J, Dienes HP, Schirmacher P, Rose-John S, Zum Buschenfelde KHM, Blessing M. TGF-beta 1 in liver fibrosis: an inducible transgenic mouse model to study liver fibrogenesis. Am J Physiol Gastrointest Liver Physiol 276: G1059-G1068, 1999.
34. Kapsenberg ML. Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol 3: 984-993, 2003.
35. Kawashima R, Mochida S, Matsui A, YouLuTu ZY, Ishikawa K, Toshima K, Yamanobe F, Inao M, Ikeda H, Ohno A, Nagoshi S, Uede T, Fujiwara K. Expression of osteopontin in Kupffer cells and hepatic macrophages and Stellate cells in rat liver after carbon tetrachloride intoxication: a possible factor for macrophage migration into hepatic necrotic areas. Biochem Biophys Res Commun 256: 527-531, 1999.
36. King TE Jr, Albera C, Bradford WZ, Costabel U, Hormel P, Lancaster L, Noble PW, Sahn SA, Szwarcberg J, Thomeer M, Valeyre D, du Bois RM. Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial. Lancet 374: 222-228, 2009.
37. Knight B, Akhurst B, Matthews VB, Ruddell RG, Ramm GA, Abraham LJ, Olvnyk JK, Yeoh GC. Attenuated liver progenitor (oval) cell and fibrogenic responses to the choline deficient, ethionine supplemented diet in the BALB/c inbred strain of mice. J Hepatol 46: 134-141, 2007.
38. Knight B, Lim R, Yeoh GC, Olynyk JK. Interferon-gamma exacerbates liver damage, the hepatic progenitor cell response and fibrosis in a mouse model of chronic liver injury. J Hepatol 47: 826-833, 2007.
39. Kremer M, Hines IN, Milton RJ, Wheeler MD. Favored T helper 1 response in a mouse model of hepatosteatosis is associated with enhanced T cell-mediated hepatitis. Hepatology 44: 216-227, 2006.
40. Kudo H, Takahara T, Yata Y, Kawai K, Zhang W, Sugiyama T. Lipopolysaccharide triggered TNF-alpha-induced hepatocyte apoptosis in a murine non-alcoholic steatohepatitis model. J Hepatol 51: 168-175, 2009.
41. Kudo H, Yata Y, Takahara T, Kawai K, Nakayama Y, Kanayama M, Oya T, Morita S, Sasahara M, Mann DA, Sugiyama T. Telmisartan attenuates progression of steatohepatitis in mice: role of hepatic macrophage infiltration and effects on adipose tissue. Liver Int 29: 988-996, 2009.
42. Kumar V. NKT-cell subsets: Promoters and protectors in inflammatory liver disease. J Hepatol 59: 618-620, 2013.
43. Langenkamp A, Messi M, Lanzavecchia A, Sallusto F. Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells. Nat Immunol 1: 311-316, 2000.
44. Larter CZ, Yeh MM. Animal models of NASH: getting both pathology and metabolic context right. J Gastroenterol Hepatol 23: 1635-1648, 2008.
45. Li X, O'Regan AW, Berman JS. IFN-gamma induction of osteopontin expression in human monocytoid cells. J Interferon Cytokine Rese 23: 259-265, 2003.
46. Li Z, Soloski MJ, Diehl AM. Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease. Hepatology 42: 880-885, 2005.
47. Locatelli I, Sutti S, Vacchiano M, Bozzola C, Albano E. NF-kappaB1 deficiency stimulates the progression of non-alcoholic steatohepatitis (NASH) in mice by promoting NKT-cell-mediated responses. Clin Sci 124: 279-287, 2013.
48. Ludwig J, Viggiano TR, McGill DB, Ott BJ. Non-alcoholic steatohepatitis - Mayo-Clinic experiences with a hitherto unnamed disease. Mayo Clinic Proceedings 55: 434-438, 1980.
49. Luo XY, Takahara T, Hou JG, Kawai K, Sugiyama T, Tsukada K, Takemoto M, Takeuchi M, Zhong L, Li XK. Theaflavin attenuates ischemia-reperfusion injury in a mouse fatty liver model. Biochem Biophys Res Commun 417: 287-293, 2012.
50. Maher JJ, Leon P, Ryan JC. Beyond insulin resistance: innate immunity in nonalcoholic steatohepatitis. Hepatology 48: 670-678, 2008.
51. Mallat A, Preaux AM, Blazejewski S, Rosenbaum J, Dhumeaux D, Mavier P. Interferon alfa and gamma inhibit proliferation and collagen synthesis of human Ito cells in culture. Hepatology 21: 1003-1010, 1995.
52. Mas E, Danjoux M, Garcia V, Carpentier S, Segui B, Levade T. IL-6 deficiency attenuates murine diet-induced non-alcoholic steatohepatitis. Plos One 4: 2009.
53. Olleros ML, Martin ML, Vesin D, Fotio AL, Santiago-Raber ML, Rubbia-Brandt L, Spahr L, Hadengue A, Garcia I. Fat diet and alcohol-induced steatohepatitis after LPS challenge in mice: role of bioactive TNF and Th1 type cytokines. Cytokine 44: 118-125, 2008.
54. Pockros PJ, Jeffers L, Afdhal N, Goodman ZD, Nelson D, Gish RG, Reddy KR, Reindollar R, Rodriguez-Torres M, Sullivan S, Blatt LM, Faris-Young S. 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 45: 569-578, 2007.
55. Radaeva S, Sun R, Jaruga B, Nguyen VT, Tian Z, Gao B. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2Ddependent and tumor necrosis factor-related apoptosis-inducing liganddependent manners. Gastroenterology 130: 435-452, 2006.
56. Rockey DC, Chung JJ. Interferon gamma inhibits lipocyte activation and extracellular matrix mRNA expression during experimental liver injury: implications for treatment of hepatic fibrosis. J Investiga Med 42: 660-670, 1994.
57. Rockey DC, Maher JJ, Jarnagin WR, Gabbiani G, Friedman SL. Inhibition of rat hepatic lipocyte activation in culture by interferongamma. Hepatology 16: 776-784, 1992.
58. Shen H, Zhang M, Minuk GY, Gong Y. Different effects of rat interferon alpha, beta and gamma on rat hepatic stellate cell proliferation and activation (Abstract). BMC Cell Biol 3: 9, 2002.
59. Shi Z, Wakil AE, Rockey DC. Strain-specific differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses. Proc Natl Acad Sci USA 94: 10663-10668, 1997.
60. Stienstra R, Saudale F, Duval C, Keshtkar S, Groener JEM, van Rooijen N, Staels B, Kersten S, Muller M. Kupffer cells promote hepatic steatosis via interleukin-1 beta-dependent suppression of peroxisome proliferator- activated receptor alpha activity. Hepatology 51: 511-522, 2010.
61. Susca M, Grassi A, Zauli D, Volta U, Lenzi M, Marchesini G, Bianchi FB, Ballardini G. Liver inflammatory cells, apoptosis, regeneration and stellate cell activation in non-alcoholic steatohepatitis. Dig Liver Dis 33: 768-777, 2001.
62. Syn WK, Agboola KM, Swiderska M, Michelotti GA, Liaskou E, Pang H, Xie G, Philips G, Chan IS, Karaca GF, Pereira Tde A, Chen Y, Mi Z, Kuo PC, Choi SS, Guy CD, Abdelmalek MF, Diehl AM. NKTassociated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. Gut 61: 1323-1329, 2012.
63. Syn WK, Oo YH, Pereira TA, Karaca GF, Jung Y, Omenetti A, Witek RP, Choi SS, Guy CD, Fearing CM, Teaberry V, Pereira FE, Adams DH, Diehl AM. Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology 51: 1998-2007, 2010.
64. Tagawa Y, Sekikawa K, Iwakura Y. Suppression of concanavalin Ainduced hepatitis in IFN-gamma(-/-) mice, but not in TNF-alpha(-/-) mice: role for IFN-gamma in activating apoptosis of hepatocytes. J Immunol 159: 1418-1428, 1997.
65. Tajiri K, Shimizu Y, Tsuneyama K, Sugiyama T. Role of liverinfiltrating CD3+CD56+ natural killer T cells in the pathogenesis of nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 21: 673-680, 2009.
66. Takahara T, Furui K, Funaki J, Nakayama Y, Itoh H, Miyabayashi C, Sato H, Seiki M, Ooshima A, Watanabe A. Increased expression of matrix metalloproteinase-ii in experimental liver fibrosis in rats. Hepatology 21: 787-795, 1995.
67. Takahashi F, Takahashi K, Maeda K, Tominaga S, Fukuchi Y. Osteopontin is induced by nitric oxide in RAW 264.7 cells. IUBMB Life 49: 217-221, 2000.
68. Takahashi K, Takahashi F, Hirama M, Tanabe KK, Fukuchi Y. Restoration of CD44S in non-small cell lung cancer cells enhanced their susceptibility to the macrophage cytotoxicity. Lung Cancer 41: 145-153, 2003.
69. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52: 1836-1846, 2010.
70. Tiniakos DG. Liver biopsy in alcoholic and non-alcoholic steatohepatitis patients. Gastroenterol Clinique et Biol 33: 930-939, 2009.
71. Tomita K, Tamiya G, Ando S, Ohsumi K, Chiyo T, Mizutani A, Kitamura N, Toda K, Kaneko T, Horie Y, Han JY, Kato S, Shimoda M, Oike Y, Tomizawa M, Makino S, Ohkura T, Saito H, Kumagai N, Nagata H, Ishii H, Hibi T. Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut 55: 415-424, 2006.
72. Tsuji H, Mukaida N, Harada A, Kaneko S, Matsushita E, Nakanuma Y, Tsutsui H, Okamura H, Nakanishi K, Tagawa Y, Iwakura Y, Kobayashi K, Matsushima K. Alleviation of lipopolysaccharide-induced acute liver injury in Propionibacterium acnes-primed IFN-gamma-deficient mice by a concomitant reduction of TNF-alpha, IL-12, and IL-18 production. J Immunol 162: 1049-1055, 1999.
73. Ulloa L, Doody J, Massague J. Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway. Nature 397: 710-713, 1999.
74. Vila-del Sol V, Diaz-Munoz MD, Fresno M. Requirement of tumor necrosis factor alpha and nuclear factor-kappaB in the induction by IFN-gamma of inducible nitric oxide synthase in macrophages. J Leukocyte Biol 81: 272-283, 2007.
75. Wallace K, Konstantinou DK, Cowie DE, Tucker SJ, Marek CJ, Durward E, Koruth M, Mann DA, Wright MC. PXR activation reduces hepatic TNF-alpha levels: a mechanism for inhibiting liver fibrosis. J Hepatol 48: S189-S189, 2008.
76. Wang Y, Mochida S, Kawashima R, Inao M, Matsui A, YouLuTu ZY, Nagoshi S, Uede T, Fujiwara K. Increased expression of osteopontin in activated Kupffer cells and hepatic macrophages during macrophage migration in Propionibacterium acnes-treated rat liver. J Gastroenterol 35: 696-701, 2000.
77. Weng H, Mertens PR, Gressner AM, Dooley S. IFN-gamma abrogates profibrogenic TGF-beta signaling in liver by targeting expression of inhibitory and receptor Smads. J Hepatol 46: 295-303, 2007.
78. Weng HL, Wang BE, Jia JD, Wu WF, Xian JZ, Mertens PR, Cai WM, Dooley S. Effect of interferon-gamma on hepatic fibrosis in chronic hepatitis B virus infection: a randomized controlled study. Clin Gastroenterol Hepatol 3: 819-828, 2005.
79. Wu YJ, Cai WM, Li Q, Liu Y, Shen H, Mertens PR, Dooley S, Weng HL. Long-term antifibrotic action of interferon-gamma treatment in patients with chronic hepatitis B virus infection. Hepatobiliary Pancreatic Dis Int 10: 151-157, 2011.
80. Yu J, Chu ES, Wang R, Wang S, Wu CW, Wong VW, Chan HL, Farrell GC, Sung JJ. Heme oxygenase-1 protects against steatohepatitis in both cultured hepatocytes and mice. Gastroenterology 138: 694-704, 2010.
81. Zhan YT, An W. Roles of liver innate immune cells in nonalcoholic fatty liver disease. World J Gastroenterol 16: 4652-4660, 2010.