Cytokines and STATs in liver fibrosis

Frontiers in Physiology

Volumn 3 APR, Issue , 2012, Pages

  Kong, Xiaoni ^a   Horiguchi, Norio ^b   Mori, Masatomo ^b   Gao, Bin ^a  

^a NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM   (United States)

^b GUNMA UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

Author keywords

Interferon; Interleukin; STATs; Stellate cells

Indexed keywords

EID: 84866337171     PISSN: None     EISSN: 1664042X     Source Type: Journal    
DOI: 10.3389/fphys.2012.00069     Document Type: Article

References (86)

1. Afdhal, N. H., McHutchison, J. G., Zeuzem, S., Mangia, A., Pawlotsky, J. M., Murray, J. S., Shianna, K. V., Tanaka, Y., Thomas, D. L., Booth, D. R., and Goldstein, D. B. (2011). Hepatitis C pharmacogenetics: state of the art in 2010. Hepatology 53, 336-345.
2. Aoudjehane, L., Pissaia, A. Jr., Scatton, O., Podevin, P., Massault, P. P., Chouzenoux, S., Soubrane, O., Calmus, Y., and Conti, F. (2008). Interleukin-4 induces the activation and collagen production of cultured human intrahepatic fibroblasts via the STAT-6 pathway. Lab. Invest. 88, 973-985.
3. Baik, M., Yu, J. H., and Hennighausen, L. (2011). Growth hormone-STAT5 regulation of growth, hepatocellular carcinoma, and liver metabolism. Ann. N. Y. Acad. Sci. 1229, 29-37.
4. Balagopal, A., Thomas, D. L., and Thio, C. L. (2010). IL28B and the control of hepatitis C virus infection. Gastroenterology 139, 1865-1876.
5. Bansal, R., Prakash, J., Post, E., Beljaars, L., Schuppan, D., and Poelstra, K. (2011). Novel engineered targeted interferon-gamma blocks hepatic fibrogenesis in mice. Hepatology 54, 586-596.
6. Barron, L., and Wynn, T. A. (2011). Fibrosis is regulated by Th2 and Th17 responses and by dynamic interactions between fibroblasts and macrophages. Am. J. Physiol. Gastrointest. Liver Physiol. 300, G723G728.
7. Bataller, R., and Brenner, D. A. (2005). Liver fibrosis. J. Clin. Invest. 115, 209-218.
8. Blaas, L., Kornfeld, J. W., Schramek, D., Musteanu, M., Zollner, G., Gumhold, J., van Zijl, F., Schneller, D., Esterbauer, H., Egger, G., Mair, M., Kenner, L., Mikulits,W., Eferl, R., Moriggl, R., Penninger, J., Trauner, M., and Casanova, E. (2010). Disruption of the growth hormone signal transducer and activator of transcription 5 insulin like growth factor 1 axis severely aggravates liver fibrosis in a mouse model of cholestasis. Hepatology 51, 1319-1326.
9. Blease, K., Schuh, J. M., Jakubzick, C., Lukacs, N. W., Kunkel, S. L., Joshi, B. H., Puri, R. K., Kaplan, M. H., and Hogaboam, C. M. (2002). Stat6-deficient mice develop airway hyperresponsiveness and peribronchial fibrosis during chronic fungal asthma. Am. J. Pathol. 160, 481-490.
10. Blindenbacher, A., Wang, X., Langer, I., Savino, R., Terracciano, L., and Heim, M. H. (2003). Interleukin 6 is important for survival after partial hepatectomy in mice. Hepatology 38, 674-682.
11. Brand, S., Dambacher, J., Beigel, F., Zitzmann, K., Heeg, M. H., Weiss, T. S., Prufer, T., Olszak, T., Steib, C. J., Storr, M., Goke, B., Diepolder, H., Bilzer, M., Thasler, W. E., and Auernhammer, C. J. (2007). IL-22mediated liver cell regeneration is abrogated by SOCS-1/3 overexpression in vitro. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G1019G1028.
12. Cao, Q., Mak, K. M., Ren, C., and Lieber, C. S. (2004). Leptin stimulates tissue inhibitor of metalloproteinase-1 in human hepatic stellate cells: respective roles of the JAK/STAT and JAKmediated H2O2-dependant MAPK pathways. J. Biol. Chem. 279, 4292-4304.
13. Chang, C. J., Chen, Y. H., Huang, K. W., Cheng, H. W., Chan, S. F., Tai, K. F., and Hwang, L. H. (2007). Combined GM-CSF and IL-12 gene therapy synergistically suppresses the growth of orthotopic liver tumors. Hepatology 45, 746-754.
14. Cheever, A. W., Williams, M. E., Wynn, T. A., Finkelman, F. D., Seder, R. A., Cox, T. M., Hieny, S., Caspar, P., and Sher, A. (1994). Anti-IL-4 treatment of Schistosoma mansoni-infected mice inhibits development of T cells and non-B, non-T cells expressing Th2 cytokines while decreasing egginduced hepatic fibrosis. J. Immunol. 153, 753-759.
15. Chiaramonte, M. G., Cheever, A. W., Malley, J. D., Donaldson, D. D., and Wynn, T. A. (2001). Studies of murine schistosomiasis reveal interleukin-13 blockade as a treatment for established and progressive liver fibrosis. Hepatology 34, 273-282.
16. Chiaramonte, M. G., Donaldson, D. D., Cheever, A. W., and Wynn, T. A. (1999a). An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2dominated inflammatory response. J. Clin. Invest. 104, 777-785.
17. Chiaramonte, M. G., Schopf, L. R., Neben, T. Y., Cheever, A. W., Donaldson, D. D., and Wynn, T. A. (1999b). IL-13 is a key regulatory cytokine for Th2 cell-mediated pulmonary granuloma formation and IgE responses induced by Schistosoma mansoni eggs. J. Immunol. 162, 920-930.
18. Cui, Y., Hosui, A., Sun, R., Shen, K., Gavrilova, O., Chen, W., Cam, M. C., Gao, B., Robinson, G. W., and Hennighausen, L. (2007). Loss of signal transducer and activator of transcription 5 leads to hepatosteatosis and impaired liver regeneration. Hepatology 46, 504-513.
19. Cussigh,A.,Falleti,E.,Fabris,C.,Bitetto, D., Cmet, S., Fontanini, E., Bignulin, S., Fornasiere, E., Fumolo, E., Minisini, R., Pirisi, M., and Toniutto, P. (2011). Interleukin 6 promoter polymorphisms influence the outcome of chronic hepatitis C. Immunogenetics 63, 33-41.
20. Dogru, T., Ercin, C. N., Erdem, G., Sonmez, A., Tapan, S., and Tasci, I. (2008). Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am. J. Gastroenterol. 103, 3217-3218.
21. Elinav, E., Ali, M., Bruck, R., Brazowski, E., Phillips, A., Shapira, Y., Katz, M., Solomon, G., Halpern, Z., and Gertler, A. (2009). Competitive inhibition of leptin signaling results in amelioration of liver fibrosis through modulation of stellate cell function. Hepatology 49, 278-286.
22. Fallon, P. G., Richardson, E. J., McKenzie, G. J., and McKenzie, A. N. (2000). Schistosome infection of transgenic mice defines distinct and contrasting pathogenic roles for IL-4 and IL-13: IL-13 is a profibrotic agent. J. Immunol. 164, 2585-2591.
23. Farah, I. O., Mola, P. W., Kariuki, T. M., Nyindo, M., Blanton, R. E., and King, C. L. (2000). Repeated exposure induces periportal fibrosis in Schistosoma mansoni-infected baboons: role of TGF-beta and IL-4. J. Immunol. 164, 5337-5343.
24. Friedbichler, K., Themanns, M., Mueller, K. M., Schlederer, M., Kornfeld, J. W., Terracciano, L. M., Kozlov, A. V., Haindl, S., Kenner, L., Kolbe, T., Mueller, M., Snibson, K. J., Heim, M. H., and Moriggl, R. (2012). Growth-hormone-induced signal transducer and activator of transcription 5 signaling causes gigantism, inflammation, and premature death but protects mice from aggressive liver cancer. Hepatology 55, 941-52.
25. Friedman, S. L. (2008). Mechanisms of hepatic fibrogenesis. Gastroenterology 134, 1655-1669.
26. Fritz, D. K., Kerr, C., Fattouh, R., Llop-Guevara, A., Khan, W. I., Jordana, M., and Richards, C. D. (2011). A mouse model of airway disease: oncostatin M-induced pulmonary eosinophilia, goblet cell hyperplasia, and airway hyperresponsiveness are STAT6 dependent, and interstitial pulmonary fibrosis is STAT6 independent. J. Immunol. 186, 1107-1118.
27. Gao, B. (2005). Cytokines, STATs and liver disease. Cell. Mol. Immunol. 2, 92-100.
28. Gao,B.,Wang,H.,Lafdil,F.,and Feng,D. (2012). STAT proteins key regulators of anti-viral responses, inflammation, and tumorigenesis in the liver. J. Hepatol. (in press).
29. Harada, N., Shimada, M., Okano, S., Suehiro, T., Soejima, Y., Tomita, Y., and Maehara, Y. (2004). IL-12 gene therapy is an effective therapeutic strategy for hepatocellular carcinoma in immunosuppressed mice. J. Immunol. 173, 6635-6644.
30. Higashiyama, R., Moro, T., Nakao, S., Mikami, K., Fukumitsu, H., Ueda,Y., Ikeda, K., Adachi, E., Bou-Gharios, G., Okazaki, I., and Inagaki, Y. (2009). Negligible contribution of bone marrow-derived cells to collagen production during hepatic fibrogenesis in mice. Gastroenterology 137, 1459-1466.
31. Honda, H., Ikejima, K., Hirose, M., Yoshikawa, M., Lang, T., Enomoto, N., Kitamura, T., Takei, Y., and Sato, N. (2002). Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver. Hepatology 36, 12-21.
32. Horiguchi, N., Lafdil, F., Miller, A. M., Park, O., Wang, H., Rajesh, M., Mukhopadhyay, P., Fu, X. Y., Pacher, P., and Gao, B. (2010). Dissociation between liver inflammation and hepatocellular damage induced by carbon tetrachloride in myeloid cellspecific signal transducer and activator of transcription 3 gene knockout mice. Hepatology 51, 1724-1734.
33. Horiguchi, N., Wang, L., Mukhopadhyay, P., Park, O., Jeong, W. I., Lafdil, F., Osei-Hyiaman, D., Moh, A., Fu, X. Y., Pacher, P., Kunos, G., and Gao, B. (2008). Cell type-dependent proand anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury. Gastroenterology 134, 1148-1158.
34. Hosui, A., Kimura, A., Yamaji, D., Zhu, B., Na, R., and Hennighausen, L. (2009). Loss of STAT5 causes liver fibrosis and cancer development through increased TGF-β and STAT3 activation. J. Exp. Med. 206, 819-831.
35. Ikejima, K., Takei,Y., Honda, H., Hirose, M., Yoshikawa, M., Zhang, Y. J., Lang, T., Fukuda, T., Yamashina, S., Kitamura, T., and Sato, N. (2002). Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. Gastroenterology 122, 1399-1410.
36. 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., and Okazaki, I. (2003). Interferon alfa down-regulates collagen gene transcription and suppresses experimental hepatic fibrosis in mice. Hepatology 38, 890-899.
37. Jeong, W. I., Park, O., Radaeva, S., and Gao, B. (2006). STAT1 inhibits liver fibrosis in mice by inhibiting stellate cell proliferation and stimulating NK cell cytotoxicity. Hepatology 44, 1441-1451.
38. Jiang, R. T. Z., Deng, L., Chen, Y., Xia, Y., Gao, Y., Wang, X., and Sun, B. (2011). Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3. Hepatology 54, 900-909.
39. Jin, Z., Sun, R., Wei, H., Gao, X., Chen, Y., and Tian, Z. (2011). Accelerated liver fibrosis in hepatitis B virus transgenic mice: involvement of natural killer T cells. Hepatology 53, 219-229.
40. Kaimori, A., Potter, J., Kaimori, J. Y., Wang, C., Mezey, E., and Koteish, A. (2007). Transforming growth factor-beta1 induces an epithelialto-mesenchymal transition state in mouse hepatocytes in vitro. J. Biol. Chem. 282, 22089-22101.
41. Kaplan, M. H. (2005). STAT4: a critical regulator of inflammation in vivo. Immunol. Res. 31, 231-242.
42. Kaplan, M. H., Whitfield, J. R., Boros, D. L., and Grusby, M. J. (1998). Th2 cells are required for the Schistosoma mansoni egg-induced granulomatous response. J. Immunol. 160, 1850-1856.
43. Ki, S. H., Park, O., Zheng, M., Morales-Ibanez, O., Kolls, J. K., Bataller, R., and Gao, B. (2010). Interleukin22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3. Hepatology 52, 1291-1300.
44. Kovalovich, K., DeAngelis, R. A., Li, W., Furth, E. E., Ciliberto, G., and Taub, R. (2000). Increased toxininduced liver injury and fibrosis in interleukin-6-deficient mice. Hepatology 31, 149-159.
45. Kroy, D. C., Beraza, N., Tschaharganeh, D. F., Sander, L. E., Erschfeld, S., Giebeler, A., Liedtke, C., Wasmuth, H. E., Trautwein, C., and Streetz, K. L. (2010). Lack of interleukin6/glycoprotein 130/signal transducers and activators of transcription-3 signaling in hepatocytes predisposes to liver steatosis and injury in mice. Hepatology 51, 463-473.
46. Lafdil, F., Wang, H., Park, O., Zhang, W., Moritoki, Y., Yin, S., Fu, X. Y., Gershwin, M. E., Lian, Z. X., and Gao, B. (2009). Myeloid STAT3 inhibits T cell-mediated hepatitis by regulating T helper 1 cytokine and interleukin-17 production. Gastroenterology 137, 2125-2135, e2121-e2122.
47. Lakner, A. M., Moore, C. C., Gulledge, A. A., and Schrum, L. W. (2010). Daily genetic profiling indicates JAK/STAT signaling promotes early hepatic stellate cell transdifferentiation. World J. Gastroenterol. 16, 5047-5056.
48. Liu, Y., Meyer, C., Müller, A., Herweck, F., Li, Q., Müllenbach, R., Mertens, P. R., Dooley, S., and Weng, H. L. (2011). IL-13 induces connective tissue growth factor in rat hepatic stellate cells via TGF-β-independent Smad signaling. J. Immunol. 187, 2814-2823.
49. Mair, M., Blaas, L., Osterreicher, C. H., Casanova, E., and Eferl, R. (2011). JAK-STAT signaling in hepatic fibrosis. Front. Biosci. 17, 2794-2811.
50. Mair, M., Zollner, G., Schneller, D., Musteanu, M., Fickert, P., Gumhold, J., Schuster, C., Fuchsbichler, A., Bilban, M., Tauber, S., Esterbauer, H., Kenner, L., Poli, V., Blaas, L., Kornfeld, J. W., Casanova, E., Mikulits, W., Trauner, M., and Eferl, R. (2010). Signal transducer and activator of transcription 3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis. Gastroenterology 138, 2499-2508.
51. Mentink-Kane, M. M., Cheever, A. W., Wilson, M. S., Madala, S. K., Beers, L. M., Ramalingam, T. R., and Wynn, T. A. (2011). Accelerated and progressive and lethal liver fibrosis in mice that lack interleukin (IL)-10, IL-12p40, and IL-13Ralpha2. Gastroenterology 141, 2200-2209.
52. Mueller, K. M., Kornfeld, J. W., Friedbichler, K., Blaas, L., Egger, G., Esterbauer, H., Hasselblatt, P., Schlederer, M., Haindl, S., Wagner, K. U., Engblom, D., Haemmerle, G., Kratky, D., Sexl, V., Kenner, L., Kozlov, A. V., Terracciano, L., Zechner, R., Schuetz, G., Casanova, E., Pospisilik, J. A., Heim,M. H.,and Moriggl,R. (2011). Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice. Hepatology 54, 1398-1409.
53. Nieto, N. (2006). Oxidative-stress and IL-6 mediate the fibrogenic effects of [corrected] Kupffer cells on stellate cells. Hepatology 44, 1487-1501.
54. Novo, E., di Bonzo, L. V., Cannito, S., Colombatto, S., and Parola, M. (2009). Hepatic myofibroblasts: a heterogeneous population of multifunctional cells in liver fibrogenesis. Int. J. Biochem. Cell Biol. 41, 2089-2093.
55. Park, O., Wang, H., Weng, H., Feigenbaum, L., Li, H., Yin, S., Ki, S. H., Yoo, S. H., Dooley, S., Wang, F. S., Young, H. A., and Gao, B. (2011). In vivo consequences of liver-specific interleukin-22 expression in mice: implications for human liver disease progression. Hepatology 54, 252-261.
56. Plum, W., Tschaharganeh, D. F., Kroy, D. C., Corsten, E., Erschfeld, S., Dierssen, U., Wasmuth, H., Trautwein, C., and Streetz, K. L. (2010). Lack of glycoprotein 130/signal transducer and activator of transcription 3-mediated signaling in hepatocytes enhances chronic liver injury and fibrosis progression in a model of sclerosing cholangitis. Am. J. Pathol. 176, 2236-2246.
57. Pockros, P. J., Jeffers, L., Afdhal, N., Goodman, Z. D., Nelson, D., Gish, R. G., Reddy, K. R., Reindollar, R., Rodriguez-Torres, M., Sullivan, S., Blatt, L. M., and Faris-Young, S. (2007). Final results of a doubleblind, placebo-controlled trial of the antifibrotic efficacy of interferongamma1b in chronic hepatitis C patients with advanced fibrosis or cirrhosis. Hepatology 45, 569-578.
58. Radaeva, S., Jaruga, B., Hong, F., Kim, W. H., Fan, S., Cai, H., Strom, S., Liu, Y., El-Assal, O., and Gao, B. (2002). Interferon-alpha activates multiple STAT signals and down-regulates cMet in primary human hepatocytes. Gastroenterology 122, 1020-1034.
59. Radaeva, S., Sun, R., Pan, H. N., Hong, F., and Gao, B. (2004). Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL22 is a survival factor for hepatocytes via STAT3 activation. Hepatology 39, 1332-1342.
60. Ramadori, G., and Christ, B. (1999). Cytokines and the hepatic acutephase response. Semin. Liver Dis. 19, 141-155.
61. Rio, A., Gassull, M. A., Aldeguer, X., Ojanguren, I., Cabre, E., and Fernandez, E. (2008). Reduced liver injury in the interleukin-6 knockout mice by chronic carbon tetrachloride administration. Eur. J. Clin. Invest. 38, 306-316.
62. Rodriguez-Galan, M. C., Reynolds, D., Correa,S. G.,Iribarren,P.,Watanabe, M., and Young, H. A. (2009). Coexpression of IL-18 strongly attenuates IL-12-induced systemic toxicity through a rapid induction of IL10 without affecting its antitumor capacity. J. Immunol. 183, 740-748.
63. Saxena, N. K., Ikeda, K., Rockey, D. C., Friedman, S. L., and Anania, F. A. (2002). Leptin in hepatic fibrosis: evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice. Hepatology 35, 762-771.
64. Schoenherr, C., Weiskirchen, R., and Haan, S. (2010). Interleukin-27 acts on hepatic stellate cells and induces signal transducer and activator of transcription 1-dependent responses. Cell Commun. Signal. 8, 19.
65. Shigekawa, M., Takehara, T., Kodama, T., Hikita, H., Shimizu, S., Li, W., Miyagi, T., Hosui, A., Tatsumi, T., Ishida, H., Kanto, T., Hiramatsu, N., and Hayashi, N. (2011). Involvement of STAT3-regulated hepatic soluble factors in attenuation of stellate cell activity and liver fibrogenesis in mice. Biochem. Biophys. Res. Commun. 406, 614-620.
66. Sripa, B., Mairiang, E., Thinkhamrop, B., Laha, T., Kaewkes, S., Sithithaworn, P., Tessana, S., Loukas, A., Brindley, P. J., and Bethony, J. M. (2009). Advanced periductal fibrosis from infection with the carcinogenic human liver fluke Opisthorchis viverrini correlates with elevated levels of interleukin-6. Hepatology 50, 1273-1281.
67. Starkel, P., De Saeger, C., Leclercq, I., Strain, A., and Horsmans, Y. (2005). Deficient Stat3 DNA-binding is associated with high Pias3 expression and a positive anti-apoptotic balance in human end-stage alcoholic and hepatitis C cirrhosis. J. Hepatol. 43, 687-695.
68. Starkel, P., Saeger, C. D., Leclercq, I., and Horsmans, Y. (2007). Role of signal transducer and activator of transcription 3 in liver fibrosis progression in chronic hepatitis C-infected patients. Lab. Invest. 87, 173-181.
69. Subleski, J. J., Hall, V. L., Back, T. C., Ortaldo, J. R., and Wiltrout, R. H. (2006). Enhanced antitumor response by divergent modulation of natural killer and natural killer T cells in the liver. Cancer Res. 66, 11005-11012.
70. Sun, R., Tian, Z., Kulkarni, S., and Gao, B. (2004). IL-6 prevents T cell-mediated hepatitis via inhibition of NKT cells in CD4+ T celland STAT3-dependent manners. J. Immunol. 172, 5648-5655.
71. Tanabe, J., Izawa, A., Takemi, N., Miyauchi, Y., Torii, Y., Tsuchiyama, H., Suzuki, T., Sone, S., and Ando, K. (2007). Interferon-beta reduces the mouse liver fibrosis induced by repeated administration of concanavalin A via the direct and indirect effects. Immunology 122, 562-570.
72. Wang, H., Lafdil, F., Kong, X., and Gao, B. (2011a). Signal transducer and activator of transcription 3 in liver diseases: a novel therapeutic target. Int. J. Biol. Sci. 7, 536-550.
73. Wang, H., Lafdil, F., Wang, L., Park, O., Yin, S., Niu, J., Miller, A. M., Sun, Z., and Gao, B. (2011b). Hepatoprotective versus oncogenic functions of STAT3 in liver tumorigenesis. Am. J. Pathol. 179, 714-724.
74. Wang, H., Lafdil, F., Wang, L., Yin, S., Feng, D., and Gao, B. (2011c). Tissue inhibitor of metalloproteinase 1 (TIMP-1) deficiency exacerbates carbon tetrachloride-induced liver injury and fibrosis in mice: involvement of hepatocyte STAT3 in TIMP1 production. Cell Biosci. 1, 14.
75. Wang, J., Leclercq, I., Brymora, J. M., Xu, N., Ramezani-Moghadam, M., London, R. M., Brigstock, D., and George,J. (2009). Kupffer cells mediate leptin-induced liver fibrosis. Gastroenterology 137, 713-723.
76. Weng, H., Mertens, P. R., Gressner, A. M., and Dooley, S. (2007). IFN-gamma abrogates profibrogenic TGF-beta signaling in liver by targeting expression of inhibitory and receptor Smads. J. Hepatol. 46, 295-303.
77. Weng, H. L., Liu, Y., Chen, J. L., Huang, T., Xu, L. J., Godoy, P., Hu, J. H., Zhou, C., Stickel, F., Marx, A., Bohle, R. M., Zimmer, V., Lammert, F., Mueller, S., Gigou, M., Samuel, D., Mertens, P. R., Singer, M. V., Seitz, H. K., and Dooley, S. (2009). The etiology of liver damage imparts cytokines transforming growth factor beta1 or interleukin-13 as driving forces in fibrogenesis. Hepatology 50, 230-243.
78. Weng, H. L., Wang, B. E., Jia, J. D., Wu, W. F., Xian, J. Z., Mertens, P. R., Cai, W. M., and Dooley, S. (2005). Effect of interferon-gamma on hepatic fibrosis in chronic hepatitis B virus infection: a randomized controlled study. Clin. Gastroenterol. Hepatol. 3, 819-828.
79. Wieckowska, A., Papouchado, B. G., Li, Z., Lopez, R., Zein, N. N., and Feldstein, A. E. (2008). Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am. J. Gastroenterol. 103, 1372-1379.
80. Wu, Y. J., Cai, W. M., Li, Q., Liu, Y., Shen, H., Mertens, P. R., Dooley, S., and Weng, H. L. (2011). Long-term antifibrotic action of interferongamma treatment in patients with chronic hepatitis B virus infection. HBPD INT 10, 151-157.
81. Wuestefeld, T., Klein, C., Streetz, K. L., Betz, U., Lauber, J., Buer, J., Manns, M. P., Muller, W., and Trautwein, C. (2003). Interleukin6/glycoprotein 130-dependent pathways are protective during liver regeneration. J. Biol. Chem. 278, 11281-11288.
82. Yang, L., Zhang, Y., Wang, L., Fan, F., Zhu, L., Li, Z., Ruan, X., Huang, H., Wang, Z., Huang, Z., Huang, Y., Yan, X., and Chen, Y. (2010). Amelioration of high fat diet induced liver lipogenesis and hepatic steatosis by interleukin-22. J. Hepatol. 53, 339-347.
83. Yoshida, K., Yang, G. X., Zhang, W., Tsuda, M., Tsuneyama, K., Moritoki, Y., Ansari, A. A., Okazaki, K., Lian, Z. X., Coppel, R. L., Mackay, I. R., and Gershwin, M. E. (2009). Deletion of interleukin-12p40 suppresses autoimmune cholangitis in dominant negative transforming growth factor beta receptor type II mice. Hepatology 50, 1494-1500.
84. Yu, J. H., Zhu, B. M., Wickre, M., Riedlinger, G., Chen, W., Hosui, A., Robinson,G.W.,and Hennighausen, L. (2010). The transcription factors signal transducer and activator of transcription 5A (STAT5A) and STAT5B negatively regulate cell proliferation through the activation of cyclin-dependent kinase inhibitor 2b (Cdkn2b) and Cdkn1a expression. Hepatology 52, 1808-1818.
85. Zenewicz, L. A., Yancopoulos, G. D., Valenzuela, D. M., Murphy, A. J., Karow, M., and Flavell, R. A. (2007). Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity 27, 647-659.
86. Zhu,R.,Diem,S.,Araujo,L. M.,Aumeunier, A., Denizeau, J., Philadelphe, E., Damotte, D., Samson, M., Gourdy, P., Dy, M., Schneider, E., and Herbelin, A. (2007). The Pro-Th1 cytokine IL-12 enhances IL-4 production by invariant NKT cells: relevance for T cell-mediated hepatitis. J. Immunol. 178, 5435-5442.