Toll-like receptors in liver fibrosis: Cellular crosstalk and mechanisms

Frontiers in Physiology

Volumn 3 MAY, Issue , 2012, Pages

  Yang, Ling ^a   Seki, Ekihiro ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Alcoholic liver disease; Cystic fibrosis; Hepatitis C; Non alcoholic steatohepatitis; Primary biliary cirrhosis; Toll like receptors

Indexed keywords

EID: 84866432939     PISSN: None     EISSN: 1664042X     Source Type: Journal    
DOI: 10.3389/fphys.2012.00138     Document Type: Review

References (168)

1. Abe, T., Kaname, Y., Hamamoto, I., Tsuda, Y., Wen, X., Taguwa, S., Mori-ishi, K., Takeuchi, O., Kawai, T., Kanto, T., Hayashi, N., Akira, S., and Matsuura, Y. (2007). Hepatitis C virus nonstructural protein 5A modulates the toll-like receptor-MyD88-dependent signaling pathway in macrophage cell lines. J. Virol. 81,8953-8966.
2. Adachi, Y., Bradford, B. U., Gao, W., Bojes, H. K., and Thurman, R. G. (1994). Inactivation of Kupf-fer cells prevents early alcohol-induced liver injury. Hepatology 20, 453-460.
3. Adachi, Y., Moore, L. E., Bradford, B. U., Gao, W., and Thurman, R. G. (1995). Antibiotics prevent liver injury in rats following long-term exposure to ethanol. Gastroenterology 108, 218-224.
4. Adawi, D., Kasravi, F. B., Molin, G., and Jeppsson, B. (1997). Effect of Lactobacillus supplementation with and without arginine on liver damage and bacterial translocation in an acute liver injury model in the rat. Hepatology 25, 642-647.
5. Ambrosini, Y. M., Yang, G. X., Zhang, W., Tsuda, M., Shu, S., Tsuneyama, K., Leung, P. S., Ansari, A. A., Coppel, R. L., and Gershwin, M. E. (2011). The multi-hit hypothesis of primary biliary cirrhosis: polyinosinic-polycytidylic acid (poly I:C) and murine autoimmune cholangitis. Clin. Exp. Immunol. 166, 110-120.
6. An, H., Hou, J., Zhou, J., Zhao, W., Xu, H., Zheng, Y., Yu, Y., Liu, S., and Cao, X. (2008). Phosphatase SHP-1 promotes TLR- and RIG-I-activated production of type I interferon by inhibiting the kinase IRAK1. Nat. Immunol. 9, 542-550.
7. Assimakopoulos, S. F., Scopa, C. D., and Vagianos, C. E. (2007a). Pathophysi-ology of increased intestinal permeability in obstructive jaundice. World J. Gastroenterol. 13, 6458-6464.
8. Assimakopoulos, S. F., Maroulis, I., Pat-soukis, N., Vagenas, K., Scopa, C. D., Georgiou, C. D., and Vagianos, C. E. (2007b). Effect of antioxi-dant treatments on the gut-liver axis oxidative status and function in bile duct-ligated rats. WorldJ. Surg. 31, 2023-2032.
9. Backhed, F., Ding, H., Wang, T., Hooper, L. V., Koh, G. Y., Nagy, A., Semenkovich, C. F., and Gordon, J. I. (2004). The gut micro-biota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. U.S.A. 101, 15718-15723.
10. Bala, S., Marcos, M., Kodys, K., Csak, T., Catalano, D., Man-drekar, P., and Szabo, G. (2011). Up-regulation of microRNA-155 in macrophages contributes to increased tumor necrosis factor {alpha} (TNF{alpha}) production via increased mRNA, half-life in alcoholic liver disease. J. Biol Chem. 286, 1436-1444.
11. Barochia, A., Solomon, S., Cui, X., Natanson, C., and Eichacker, P. Q. (2011). Eritoran tetrasodium (E5564) treatment for sepsis: review of preclinical and clinical studies. Expert Opin. Drug Metab. Toxicol. 7, 479-494.
12. Bataller, R., and Brenner, D. A. (2005). Liver fibrosis. J. Clin. Invest. 115, 209-218.
13. Belinda, L. W., Wei, W X., Hanh, B. T., Lei, L. X., Bow, H., and Ling, D. J. (2008). SARM: a novel toll-like receptor adaptor, is functionally conserved from arthropod to human. Mol Immunol. 45, 1732-1742.
14. Berres, M. L., Koenen, R. R., Rueland, A., Zaldivar, M. M., Heinrichs, D., Sahin, H., Schmitz, P., Streetz, K. L., Berg, T., Gassler, N., Weiskirchen, R., Proud-foot, A., Weber, C., Trautwein, C., and Wasmuth, H. E. (2010). Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice.J. Clin. Invest. 120,4129-4140.
15. Bode, C., Kugler, V., and Bode, J. C. (1987). Endotoxemia in patients with alcoholic and non-alcoholic cirrhosis and in subjects with no evidence of chronic liver disease following acute alcohol excess. J. Hepatol. 4,8-14.
16. Chang, S., Dolganiuc, A., and Szabo, G. (2007). Toll-like receptors 1 and 6 are involved in TLR2-mediated macrophage activation by hepatitis C virus core and NS3 proteins. J. Leukoc. Biol. 82, 479-487.
17. Chen, Y., Yang, F., Lu, H., Wang, B., Lei, D., Wang, Y., Zhu, B., and Li, L. (2011). Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 54, 562-572.
18. Chen, Z., Cheng, Y., Xu, Y., Liao, J., Zhang, X., Hu, Y., Zhang, Q., Wang, J., Zhang, Z., Shen, F., and Yuan, Z. (2008). Expression profiles and function of toll-like receptors 2 and 4 in peripheral blood mononuclear cells of chronic hepatitis B patients. Clin. Immunol. 128, 400-408.
19. Chockalingam, A., Cameron, J. L., Brooks, J. C., and Leifer, C. A. (2011). Negative regulation of signaling by a soluble form of toll-like receptor 9. Em. I Immunol. 41, 2176-2184.
20. Coenen, M., Nischalke, H. D., Kramer, B., Langhans, B., Glassner, A., Schulte, D., Korner, C., Sauerbruch, T., Nattermann, J., and Spengler, U. (2011). Hepatitis C virus core protein induces fibrogenic actions of hepatic stellate cells via toll-like receptor 2. Lab. Invest. 91, 1375-1382.
21. Coll, R. C., and O'Neill, L. A. (2010). New insights into the regulation of signalling by toll-like receptors and nod-like receptors. J. Innate Immun. 2,406-421.
22. Connolly, M. K., Bedrosian, A. S., Mallen-St Clair, J., Mitchell, A. P., Ibrahim, J., Stroud, A., Pachter, H. L., Bar-Sagi, D., Frey, A. B., and Miller, G. (2009). In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-alpha. J. Clin. Invest. 119,3213-3225.
23. Crispe, I. N. (2009). The liver as a lym-phoid organ. Annu. Rev. Immunol. 27,147-163.
24. Csak, T., Velayudham, A., Hritz, I., Petrasek, J., Levin, I., Lippai, D., Catalano, D., Mandrekar, P., Dolganiuc, A., Kurt-Jones, E., and Szabo, G. (2011). Deficiency in myeloid differentiation factor-2 and toll-like receptor 4 expression attenuates nonalcoholic steatohepatitis and fibrosis in mice. Am. J. Physiol. Gas-trointest. Liver Physiol. 300, G433-G441.
25. Doi, H., Iyer, T. K., Carpenter, E., Li, H., Chang, K. M., Vonderheide, R. H., and Kaplan, D. E. (2012). Dysfunctional B-cell activation in cirrhosis due to hepatitis C infection associated with disappearance of CD27+ B-cell population. Hepatology 55, 709-719.
26. Dolganiuc, A., Oak,S.,Kodys,K.,Golen-bock, D. T., Finberg, R. W., Kurt-Jones, E., and Szabo, G. (2004). Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation. Gastroenterology 127, 1513-1524.
27. Eksioglu, E. A., Zhu, H., Bayouth, L., Bess, J., Liu, H. Y., Nelson, D. R., and Liu, C. (2011). Characterization of HCV interactions with toll-like receptors and RIG-I in liver cells. PLoS ONE 6, e21186. doi:10.1371/journal.pone.0021186
28. Ewaschuk, J., Endersby, R., Thiel, D., Diaz, H., Backer, J., Ma, M., Churchill,T.,andMadsen,K. (2007). Probiotic bacteria prevent hepatic damage and maintain colonic barrier function in a mouse model of sepsis. Hepatology 46, 841-850.
29. Fenhammar, J., Rundgren, M., Forestier, J., Kalman, S., Eriksson, S., and Frithiof, R. (2011). Toll-like receptor 4 inhibitor TA, K-242 attenuates acute kidney injury in endo-toxemic sheep. Anesthesiology 114, 1130-1137.
30. Fiorotto, R., Scirpo, R., Trauner, M., Fabris, L., Hoque, R., Spirli, C., and Strazzabosco, M. (2011). Loss of CFTR, affects biliary epithelium innate immunity and causes TLR4-NF-kappaB-mediated inflammatory response in mice. Gastroenterology 141, 1498-1508; 1508.e1-5.
31. Fort, M. M., Mozaffarian, A., Stover, A. G., Correia Jda, S., Johnson, D. A., Crane, R. T., Ulevitch, R. J., Persing, D. H., Bielefeldt-Ohmann, H., Probst, P., Jeffery, E., Fling, S. P., and Hershberg, R. M. (2005). A synthetic TL, R4 antagonist has anti-inflammatory effects in two murine models of inflammatory bowel disease.J. Immunol. 174, 6416-6423.
32. Foy, E., Li, K., Sumpter, R. Jr., Loo, Y M., Johnson, C. L., Wang, C., Fish, P. M., Yoneyama, M., Fujita, T., Lemon, S. M., and Gale, M. Jr. (2005). Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. Proc. Natl. Acad. Sci. U.S.A. 102,2986-2991.
33. Frances, R., Benlloch, S., Zapater, P., Gonzalez, J. M., Lozano, B., Munoz, C., Pascual, S., Casellas, J. A., Uceda, F., Palazon, J. M., Carnicer, E, Perez-Mateo, M., and Such, J. (2004). A sequential study of serum bacterial DNA in patients with advanced cirrhosis and ascites. Hepatology 39, 484-491.
34. Frances, R., Zapater, P., Gonzalez-Navajas, C., Munoz, R., Cano, R., Moreu, S., Pascual, S., Bellot, P., Perez-Mateo, M., and Such, J. (2008). Bacterial DNA in patients with cirrhosis and noninfected ascites mimics the soluble immune response established in patients with spontaneous bacterial peritonitis. Hepatology 47, 978-985.
35. Friedman, S. L. (2008). Mechanisms of hepatic fibrogenesis. Gastroenterology 134,1655-1669.
36. Friedman, S. L. (2010). Evolving challenges in hepatic fibrosis. Nat. Rev. Gastroenterol. Hepatol. 7, 425-436.
37. Fukui, H., Brauner, B., Bode, J. C., and Bode, C. (1991). Plasma endotoxin concentrations in patients with alcoholic and non-alcoholic liver disease: reevaluation with an improved chromogenic assay. J. Hepatol. 12, 162-169.
38. Gabele, E., Dostert, K., Hofmann, C., Wiest, R., Scholmerich, J., Hellerbrand, C., and Obermeier, E (2011a). DSS induced colitis increases portal LPS levels and enhances hepatic inflammation and fibrogenesis in experimental NASH. J. Hepatol. 55, 1391-1399.
39. Gabele, E., Dostert, K., Dorn, C., Pat-senker, E., Stickel, F., and Hellerbrand, C. (2011b). A new model of interactive effects of alcohol and high-fat diet on hepatic fibrosis. Alcohol. Clin. Exp. Res. 35, 1361-1367.
40. Gabele, E., Muhlbauer, M., Dorn, C., Weiss, T. S., Froh, M., Schn-abl, B., Wiest, R., Scholmerich, J., Obermeier, F., and Hellerbrand, C. (2008). Role of TLR9 in hepatic stellate cells and experimental liver fibrosis. Biochem. Biophys. Res. Com-mun. 376,271-276.
41. Gilchrist, M., Thorsson, V., Li, B., Rust, A. G., Korb, M., Roach, J. C., Kennedy, K., Hai, T., Bolouri, H., and Aderem, A. (2006). Systems biology approaches identify ATF3 as a negative regulator of toll-like receptor 4. Nature 441,173-178.
42. Goldfarb, R. D., Ortegel, J. W., Par-rillo, J. E., Zanotti-Cavazzoni, S., Casey, L. C., and Dellinger, R. P. (2011). TAKEDA-143242 increased survival via reduced cytokines in porcine peritonitis. J. Surg. Res. 166, e165-e173.
43. Gomez-Hurtado, I., Santacruz, A., Peiro, G., Zapater, P., Gutierrez, A., Perez-Mateo, M., Sanz, Y., and Frances, R. (2011). Gut micro-biota dysbiosis is associated with inflammation and bacterial translo-cation in mice with CCl(4)-induced fibrosis. PLoS ONE 6, e23037. doi:10.1371/journal.pone.0023037
44. Grinko, I., Geerts, A., and Wisse, E. (1995). Experimental biliary fibrosis correlates with increased numbers of fat-storing and Kupffer cells, and portal endotoxemia. J. Hepatol. 23, 449-458.
45. Guan, Y., Ranoa, D. R., Jiang, S., Mutha, S. K., Li, X., Baudry, J., and Tapping, R. I. (2010). Human TLRs 10 and 1 share common mechanisms of innate immune sensing but not signaling. J. Immunol. 184, 5094-5103.
46. Guarner, C., Gonzalez-Navajas, J. M., Sanchez, E., Soriando, G., Frances, R., Chiva, M., Zapater, P., Benlloch, S., Munoz, C., Pascual, S., Balanzo, J., Perez-Mateo, M., and Such, J. (2006). The detection of bacterial DNA in blood of rats with CCl4-induced cirrhosis with ascites represents episodes of bacterial transloca-tion. Hepatology 44, 633-639.
47. Guarner, C., Runyon, B. A., Young, S., Heck, M., and Sheikh, M. Y (1997). Intestinal bacterial overgrowth and bacterial translocation in cirrhotic rats with ascites. J. Hepatol. 26, 1372-1378.
48. Guarner-Argente, C., Sanchez, E., Vidal, S., Roman, E., Concepcion, M., Poca, M., Sanchez, D., Juarez, C., Soriano, G., and Guarner, C. (2010). Toll-like receptor 4 D299G polymorphism and the incidence of infections in cirrhotic patients. Aliment. Pharmacol. Ther. 31, 1192-1199.
49. Guo, J., and Friedman, S. L. (2010). Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis. Fibrogenesis Tissue Repair 3, 21.
50. Guo, J., Loke, J., Zheng, F., Hong, F., Yea, S., Fugita, M., Tarocchi, M., Abar, O. T., Huang, H., Sninsky, J. J., and Friedman, S. L. (2009). Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of toll-like receptor 4 to hepatic stellate cell responses. Hepatology 49, 960-968.
51. Hacker, H., Redecke, V., Blagoev, B., Kratchmarova, I., Hsu, L. C., Wang, G. G., Kamps, M. P., Raz, E., Wagner, H., Hacker, G., Mann, M., and Karin, M. (2006). Specificity in toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature 439, 204-207.
52. Harada, K., Isse, K., Sato, Y., Ozaki, S., and Nakanuma, Y. (2006). Endotoxin tolerance in human intrahep-atic biliary epithelial cells is induced by upregulation of IRAK-M. Liver Int. 26, 935-942.
53. Harada, K., and Nakanuma, Y. (2010a). Biliary innate immunity: function and modulation. Mediators Inflamm. 2010, 9.
54. Harada, K., and Nakanuma, Y. (2010b). Biliary innate immunity in the pathogenesis of biliary diseases. Inflamm. Allergy Drug Targets 9, 83-90.
55. He, Q., Graham, C. S., Durante Mangoni, E., and Koziel, M. J. (2006). Differential expression of toll-like receptor mRNA, in treatment non-responders and sustained virologic responders at baseline in patients with chronic hepatitis C. Liver Int. 26,1100-1110.
56. Hritz, I.,Mandrekar, P.,Velayudham,A., Catalano, D., Dolganiuc, A., Kodys, K., Kurt-Jones, E., and Szabo, G. (2008a). The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88. Hepatol-ogy 48,1224-1231.
57. Hritz, I., Velayudham, A., Dolganiuc, A., Kodys, K., Mandrekar, P., Kurt-Jones, E., and Szabo, G. (2008b). Bone marrow-derived immune cells mediate sensitization to liver injury in a myeloid differentiation factor 88-dependent fashion. Hepatology 48,1342-1347.
58. Huang, H., Shiffman, M. L., Friedman, S., Venkatesh, R., Bzowej, N., Abar, O. T., Rowland, C. M., Catanese, J. J., Leong, D. U., Sninsky, J. J., Layden, T. J., Wright, T. L., White, T., and Cheung, R. C. (2007). A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C. Hepatology 46, 297-306.
59. Imamura, M., Tsutsui, H., Yasuda, K., Uchiyama, R., Yumikura-Futatsugi, S., Mitani, K., Hayashi, S., Akira, S., Taniguchi, S., Van Rooijen, N., Tschopp, J., Yamamoto, T., Fujimoto, J., and Nakanishi, K. (2009). Contribution of TIR domain-containing adapter inducing IFN-beta-mediated IL-18 release to LPS-induced liver injury in mice. J.Hepatol. 51,333-341.
60. Inokuchi, S., Tsukamoto, H., Park, E. J., Liu, Z.-X., Brenner, D. A., and Seki, E. (2011). Toll-like receptor 4 mediates alcohol-induced steatohepatitis through bone marrow-derived and endogenous liver cells in mice. Alcohol. Clin. Exp. Res. 35,1509-1518.
61. LPS signaling enhances hepatic fibrogenesis caused by experimental cholestasis in mice
62. Isogawa, M., Robek, M. D., Furuichi, Y., and Chisari, F. V. (2005). Toll-like receptor signaling inhibits hepatitis B virus replication in vivo. J. Virol. 79, 7269-7272.
63. Jagavelu, K., Routray, C., Shergill, U., O'Hara, S. P., Faubion, W., and Shah, V. H. (2010). Endothelial cell toll-like receptor 4 regulates fibrosis-associated angiogenesis in the liver. Hepatology 52,590-601.
64. Jeong,W.I.,Park,O.,andGao,B. (2008). Abrogation of the antifibrotic effects of natural killer cells/interferon-gamma contributes to alcohol acceleration of liver fibrosis. Gastroen-terology 134,248-258.
65. 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.
66. Jeong, W.-I., Park, O., Suh, Y.-G., Byun, J.-S., Park, S.-Y., Choi, E., Kim, J.-K., Ko, H., Wang, H., Miller, A. M., and Gao, B. (2011). Suppression of innate immunity (natural killer cell/interferon-γ) in the advanced stages of liver fibrosis in mice. Hepatology 53,1342-1351.
67. Kagan, J. C., Su, T., Horng, T., Chow, A., Akira, S., and Medzhitov, R. (2008). TRAM, couples endocytosis of toll-like receptor 4 to the induction of interferon-beta. Nat. Immunol. 9, 361-368.
68. Kawai, T., and Akira, S. (2010). The role of pattern-recognition receptors in innate immunity: update on toll-like receptors. Nat. Immunol. 11, 373-384.
69. Kikuchi, K., Lian, Z. X., Yang, G. X., Ansari, A. A., Ikehara, S., Kaplan, M., Miyakawa, H., Coppel, R. L., and Gershwin, M. E. (2005a). Bacterial CpG, induces hyper-IgM, production in CD, 27(+) memory B cells in primary biliary cirrhosis. Gastroenterology 128,304-312.
70. Kikuchi, K., Lian, Z. X., Kimura, Y., Selmi, C., Yang, G. X., Gordon, S. C., Invernizzi, P., Podda, M., Cop-pel, R. L., Ansari, A. A., Ikehara, S., Miyakawa, H., and Gershwin, M. E. (2005b). Genetic polymorphisms of toll-like receptor 9 influence the immune response to CpG, and contribute to hyper-IgM, in primary biliary cirrhosis. J. Autoimmun. 24, 347-352.
71. Kitazawa, T., Tsujimoto, T., Kawaratani, H., and Fukui, H. (2010). Salvage effect of E5564, toll-like receptor 4 antagonist on d-galactosamine and lipopolysaccharide-induced acute liver failure in rats. J. Gastroenterol. Hepatol. 25,1009-1012.
72. Kobayashi, K., Hernandez, L. D., Galan, J. E., Janeway, C. A. Jr., Medzhitov, R., and Flavell, R. A. (2002). IRAK-M is a negative regulator of toll-like receptor signaling. Cell 110, 191-202.
73. Lang, T., Lo, C., Skinner, N., Locarnini, S., Visvanathan, K., and Mansell, A. (2011). The hepatitis B e antigen (HBeAg) targets and suppresses activation of the toll-like receptor signaling pathway. J. Hepatol. 55, 762-769.
74. Ley, R. E., Turnbaugh, P. J., Klein, S., and Gordon, J. I. (2006). Micro-bial ecology: human gut microbes associated with obesity. Nature 444, 1022-1023.
75. Li, K., Foy, E., Ferreon, J. C., Nakamura, M., Ferreon, A. C., Ikeda, M., Ray, S. C., Gale, M. Jr., and Lemon, S. M. (2005). Immune evasion by hepatitis C virus NS, 3/4A protease-mediated cleavage of the toll-like receptor 3 adaptor protein TRIF. Proc. Natl. Acad. Sci. U.S.A. 102,2992-2997.
76. Li, L., Chen, L., Hu, L., Liu, Y., Sun, H. Y., Tang, J., Hou, Y J., Chang, Y. X., Tu, Q. Q., Feng, G. S., Shen, E, Wu, M. C., and Wang, H. Y. (2011). Nuclear factor high-mobility group box1 mediating the activation of toll-like receptor 4 signaling in hepatocytes in the early stage of nonalcoholic fatty liver disease in mice. Hepatology 54, 1620-1630.
77. Li, K., Li, N. L., Wei, D., Pfeffer, S. R., Fan, M., and Pfeffer, L. M. (2012). Activation of chemokine and inflammatory cytokine response in HCV-infected hepatocytes depends on TLR3 sensing of HCV dsRNA intermediates. Hepatology 55, 666- 675.
78. Li, Z., Yang, S., Lin, H., Huang, J., Watkins, P. A., Moser, A. B., Des-imone, C., Song, X. Y., and Diehl, A. M. (2003). Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 37, 343-350.
79. Lian, J. Q., Wang, X. Q., Zhang, Y., Huang, C. X., and Bai, X. F. (2009). Correlation of circulating TLR2/4 expression with CD, 3+/4+/8+. T cells and Treg cells in HB, V-related liver cirrhosis. Viral Immunol. 22, 301-308.
80. Liew, F. Y., Xu, D., Brint, E. K., and O'Neill, L. A. (2005). Negative regulation of toll-like receptor-mediated immune responses. Nat. Rev. Immunol. 5, 446-458.
81. Liu, Q., Duan, Z. P., Ha, D. K., Beng-mark, S., Kurtovic, J., and Riordan, S. M. (2004). Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 39, 1441-1449.
82. Loguercio, C., Federico, A., Tuccillo, C., Terracciano, F., D'Auria, M. V., De Simone, C., and Del Vecchio Blanco C. (2005). Beneficial effects of apro-biotic VS, L#3 on parameters of liver dysfunction in chronic liver diseases. J. Clin. Gastroenterol. 39, 540-543.
83. Loo, Y M., Owen, D. M., Li, K., Erickson, A. K., Johnson, C. L., Fish, P. M., Carney, D. S., Wang, T., Ishida, H., Yoneyama, M., Fujita, T., Saito, T., Lee, W M., Hagedorn, C. H., Lau, D.T., Weinman, S. A., Lemon, S. M., and Gale, M. Jr. (2006). Viral and therapeutic control of IFN-beta pro moter stimulator 1 during hepatitis C virus infection. Proc. Natl. Acad. Sci. U.S.A. 103,6001-6006.
84. Lu, H., Wu, Z., Xu, W., Yang, J., Chen, Y., and Li, L. (2011). Intestinal microbiota was assessed in cirrhotic patients with hepatitis B virus infection. Intestinal microbiota of HBV cirrhotic patients. Microb. Ecol. 61, 693-703.
85. Ma, R., Du, J. L., Huang, J., and Wu, C. Y (2007). Additive effects of CpG ODN and R-848 as adjuvants on augmenting immune responses to HBsAg vaccination. Biochem. Bio-phys. Res. Commun. 361,537-542.
86. Machida, K., Cheng, K. T., Sung, V. M., Levine, A. M., Foung, S., and Lai, M. M. (2006). Hepatitis C virus induces toll-like receptor 4 expression, leading to enhanced production of beta interferon and interleukin-6. J. Virol. 80, 866-874.
87. Mandal, P., Roychowdhury, S., Park, P. H., Pratt, B. T., Roger, T., and Nagy, L. E. (2010). Adiponectin and heme oxygenase-1 suppress TLR4/MyD, 88-independent signaling in rat Kupffer cells and in mice after chronic ethanol exposure. J. Immunol. 185,4928-4937.
88. Manigold, T., Bocker, U., Hanck, C., Gundt, J., Traber, P., Antoni, C., and Rossol, S. (2003). Differential expression of toll-like receptors 2 and 4 in patients with liver cirrhosis. Eur. J. Gastroenterol. Hepatol. 15, 275-282.
89. Mao, T. K., Lian, Z. X., Selmi, C., Ichiki, Y., Ashwood, P., Ansari, A. A., Coppel, R. L., Shimoda, S., Ishibashi, H., and Gershwin, M. E. (2005). Altered monocyte responses to defined TLR ligands in patients with primarybiliary cirrhosis. Hepatology 42,802-808.
90. Marra, F.,Romanelli,R. G.,Giannini, C., Failli, P., Pastacaldi, S., Arrighi, M. C., Pinzani, M., Laffi, G., Montalto, P., and Gentilini, P. (1999). Monocyte chemotactic protein-1 as a chemoat-tractant for human hepatic stellate cells. Hepatology 29,140-148.
91. Matsunaga, N., Tsuchimori, N., Mat-sumoto, T., and Ii, M. (2011). TAK-242 (resatorvid), a small-molecule inhibitor of toll-like receptor (TLR) 4 signaling, binds selectively to TLR4 and interferes with interactions between TLR4 and its adaptor molecules. Mol. Pharmacol. 79, 34-41.
92. Matsushita, K., Takeuchi, O., Stand-ley, D. M., Kumagai, Y., Kawa-goe, T., Miyake, T., Satoh, T., Kato, H., Tsujimura, T., Nakamura, H., and Akira, S. (2009). Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA, decay. Nature 458, 1185-1190.
93. Meylan, E., Curran, J., Hofmann, K., Moradpour, D., Binder, M., Barten-schlager, R., and Tschopp, J. (2005). Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437, 1167-1172.
94. Miura, K., Kodama, Y., Inokuchi, S., Schnabl, B., Aoyama, T., Ohnishi, H., Olefsky, J. M., Brenner, D. A., and Seki, E. (2010). Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology 139, 323-34 e7.
95. Moritoki, Y., Lian, Z. X., Wulff, H., Yang, G. X., Chuang, Y H., Lan, R. Y., Ueno, Y., Ansari, A. A., Cop-pel, R. L., Mackay, I. R., and Gershwin, M. E. (2007). AM, A production in primary biliary cirrhosis is promoted by the TLR9 ligand CpG, and suppressed by potassium channel blockers. Hepatology 45, 314-322.
96. Nakagawa, R., Naka, T., Tsutsui, H., Fuji-moto, M., Kimura, A., Abe, T., Seki, E., Sato, S., Takeuchi, O., Takeda, K., Akira, S., Yamanishi, K., Kawase, I., Nakanishi, K., and Kishimoto, T. (2002). SOCS-1 participates in negative regulation of LPS responses. Immunity 17, 677-687.
97. Nanji, A. A., Khettry, U., and Sadrzadeh, S. M. (1994). Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver (disease). Proc. Soc. Exp. Biol Med. 205, 243-247.
98. Naveau, S., Giraud, V., Borotto, E., Aubert, A., Capron, F., and Chaput, J. C. (1997). Excess weight risk factor for alcoholic liver disease. Hepatology 25,108-111.
99. Nolan, J. P., and Leibowitz, A. I. (1978). Endotoxin and the liver. III Modification of acute carbon tetrachloride injury by polymyxin b - an antiendotoxin. Gastroenterol-ogy 75, 445-449.
100. O'Neill, L. A., Sheedy, F. J., and McCoy, C. E. (2011). MicroRNAs: the fine-tuners of toll-like receptor signalling. Nat. Rev. Immunol. 11, 163-175.
101. Osman, N., Adawi, D., Ahrne, S., Jepps-son, B., and Molin, G. (2007). Endotoxin- and D-galactosamine-induced liver injury improved by the administration of Lactobacillus, Bifidobacterium and blueberry. Dig. Liver Dis. 39, 849-856.
102. Otsuka, M., Kato, N., Moriyama, M., Taniguchi, H., Wang, Y., Dharel, N., Kawabe, T., and Omata, M. (2005). Interaction between the HCV NS3 protein and the host TBK1 protein leads to inhibition of cellular antiviral responses. Hepatology 41, 1004-1012.
103. Paik, Y H., Lee, K. S., Lee, H. J., Yang, K. M., Lee, S. J., Lee, D. K., Han, K. H., Chon, C. Y., Lee, S. I., Moon, Y. M., and Brenner, D. A. (2006). Hepatic stellate cells primed with cytokines upregulate inflammation in response to peptidoglycan or lipoteichoic acid. Lab. Invest. 86, 676-686.
104. Paik, Y. H., Schwabe, R. F., Bataller, R., Russo, M. P., Jobin, C., and Brenner, D. A. (2003). Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccha-ride in human hepatic stellate cells. Hepatology 37,1043-1055.
105. Petrasek,J.,Dolganiuc,A.,Csak,T.,Nath, B., Hritz, I., Kodys, K., Catalano, D., Kurt-Jones, E., Mandrekar, P., and Szabo, G. (2011). Interferon regulatory factor 3 and type I interferons are protective in alcoholic liver injury in mice by way of crosstalk of parenchy-malandmyeloidcells.Hepatology53, 649-660.
106. Quinn, S. R., and O'Neill, L. A. (2011). A trio of microRNAs that control toll-like receptor signalling. Int. Immunol. 23,421-425.
107. Radaeva, S., Sun, R., Jaruga, B., Nguyen, V. T., Tian, Z., and Gao, B. (2006). 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 130,435-452.
108. Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S., and Medzhitov, R. (2004). Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118, 229-241.
109. Rayes, N., Seehofer, D., Hansen, S., Boucsein, K., Muller, A. R., Serke, S., Bengmark, S., and Neuhaus, P. (2002). Early enteral supply of lactobacillus and fiber versus selective bowel decontamination: a controlled trial in liver transplant recipients. Transplantation 74,123-127.
110. Rayes, N., Seehofer, D., Theruvath, T., Schiller, R. A., Langrehr, J. M., Jonas, S., Bengmark, S., and Neuhaus, P. (2005). Supply of pre- and probi-otics reduces bacterial infection rates after liver transplantation - a randomized, double-blind trial. Am. J. Transplant. 5,125-130.
111. Riordan, S. M., Skinner, N., Nagree, A., McCallum, H., McIver, C. J., Kur-tovic, J., Hamilton, J. A., Bengmark, S., Williams, R., and Visvanathan, K. (2003). Peripheral blood mononu-clear cell expression of toll-like receptors and relation to cytokine levels in cirrhosis. Hepatology 37, 1154-1164.
112. Rivera, C. A., Adegboyega, P., van Rooijen, N., Tagalicud, A., Allman, M., and Wallace, M. (2007). Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the patho-genesis of non-alcoholic steatohepatitis. J. Hepatol. 47, 571-579.
113. Rivera, C. A., Gaskin, L., Allman, M., Pang, J., Brady, K., Adegboyega, P., and Pruitt, K. (2010). Toll-like receptor-2 deficiency enhances non-alcoholic steatohepatitis. BMC Gastroenterol. 10, 52. doi:10.1186/1471-230X-10-52
114. Roderburg, C., Urban, G. W., Better-mann, K., Vucur, M., Zimmermann, H., Schmidt, S., Janssen, J., Koppe, C., Knolle, P., Castoldi, M., Tacke, E, Trautwein, C., and Luedde, T. (2011). MicroRNA profiling reveals a role for miR-29 in human and murine liver fibrosis. Hepatology 53, 209-218.
115. Saito, T., Owen, D. M., Jiang, F., Marcotrigiano, J., and Gale, M. Jr. (2008). Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature 454, 523-527.
116. Saitoh, S., Akashi, S., Yamada, T., Tan-imura, N., Kobayashi, M., Konno, K., Matsumoto, F., Fukase, K., Kusumoto, S., Nagai, Y., Kusumoto, Y., Kosugi, A., and Miyake, K. (2004). Lipid A antagonist, lipid IVa, is distinct from lipid A in interaction with toll-like receptor 4 (TLR4)-MD-2 and ligand-induced TLR4 oligomer-ization. Int. Immunol. 16, 961-969.
117. Sato, K., Ishikawa, T., Okumura, A., Yamauchi, T., Sato, S., Ayada, M., Matsumoto, E., Hotta, N., Oohashi, T., Fukuzawa, Y., and Kakumu, S. (2007). Expression of toll-like receptors in chronic hepatitis C virus infection. J. Gastroenterol. Hepatol. 22,1627-1632.
118. Schnabl, B., Brandl, K., Fink, M., Gross, P., Taura, K., Gabele, E., Heller-brand, C., and Falk, W (2008). A TLR4/MD2 fusion protein inhibits LPS-induced pro-inflammatory signaling in hepatic stellate cells. Biochem. Biophys. Res. Commun. 375,210-214.
119. Schott, E., Witt, H., Neumann, K., Taube, S., Oh, D. Y., Schreier, E., Vierich, S., Puhl, G., Bergk, A., Halangk, J., Weich, V., Wieden-mann, B., and Berg, T. (2007). A toll-like receptor 7 single nucleotide polymorphism protects from advanced inflammation and fibrosis in male patients with chronic HCV-infection. J. Hepatol. 47, 203-211.
120. Schwabe, R. F., Bataller, R., and Brenner, D. A. (2003). Human hepatic stellate cells express CCR5 and RANTES, to induce proliferation and migration. Am. J. Physiol. Gastrointest. Liver Physiol. 285, G949-G958.
121. Seki, E., and Brenner, D. A. (2008). Toll-like receptors and adaptor molecules in liver disease: update. Hepatology 48, 322-335.
122. Seki, E., de Minicis, S., Inokuchi, S., Taura, K., Miyai, K., van Rooijen, N., Schwabe, R. F., and Brenner, D. A. (2009a). CCR2 promotes hepatic fibrosis in mice. Hepatology 50, 185-197.
123. Seki, E., De Minicis, S., Gwak, G. Y., Kluwe, J., Inokuchi, S., Bursill, C. A., Llovet, J. M., Brenner, D. A., and Schwabe, R. F. (2009b). CCR1 and CCR5 promote hepatic fibrosis in mice.J. Clin. Invest. 119,1858-1870.
124. Seki, E., De Minicis, S., Osterreicher, C. H., Kluwe, J., Osawa, Y., Brenner, D. A., and Schwabe, R. E (2007). TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat. Med. 13, 1324-1332.
125. Seki, E., and Schnabl, B. (2012). Role of innate immunity and the microbiota in liver fibrosis - crosstalk between the liver and gut. J. Physiol. (Lond.) 590,447-458.
126. Seki, E., Tsutsui, H., Nakano, H., Tsuji, N., Hoshino, K., Adachi, O., Adachi, K., Futatsugi, S., Kuida, K., Takeuchi, O., Okamura, H., Fuji-moto, J., Akira, S., and Nakanishi, K. (2001).Lipopolysaccharide-induced IL-18 secretion from murine Kupffer cells independently of myeloid differentiation factor 88 that is critically involved in induction of production of IL-12 and IL-1beta. J. Immunol. 166,2651-2657.
127. Seki, E., Tsutsui, H., Tsuji, N. M., Hayashi, N., Adachi, K., Nakano, H., Futatsugi-Yumikura, S., Takeuchi, O., Hoshino, K., Akira, S., Fuji-moto, J., and Nakanishi, K. (2002). Critical roles of myeloid differentiation factor 88-dependent proin-flammatory cytokine release in early phase clearance of Listeria monocy-togenes in mice. J. Immunol. 169, 3863-3868.
128. Sha, T., Sunamoto, M., Kitazaki, T., Sato, J., Ii, M., andIizawa, Y. (2007). Therapeutic effects of TAK-242, a novel selective toll-like receptor 4 signal transduction inhibitor, in mouse endotoxin shock model. Eur. J. Pharmacol. 571, 231-239.
129. Sheedy, F. J., Palsson-McDermott, E., Hennessy, E. J., Martin, C., O'Leary, J. J., Ruan, Q., Johnson, D. S., Chen, Y., and O'Neill, L. A. (2010). Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA, miR-21. Nat. Immunol. 11, 141-147.
130. Shehata, M. A., Abou El-Enein, A., and El-Sharnouby, G. A. (2006). Significance of toll-like receptors 2 and 4 mRNA, expression in chronic hepatitis C virus infection. Egypt J. Immunol. 13, 141-152.
131. Shiina, M., and Rehermann, B. (2008). Cell culture-produced hepatitis C virus impairs plasmacytoid dendritic cell function. Hepatology 47, 385-395.
132. Shimoda, S., Harada, K., Niiro, H., Shirabe, K., Taketomi, A., Maehara, Y., Tsuneyama, K., Nakanuma, Y., Leung, P., Ansari, A. A., Gershwin, M. E., and Akashi, K. (2011). Interaction between toll-like receptors and natural killer cells in the destruction of bile ducts in primary biliary cirrhosis. Hepatology 53, 1270-1281.
133. Soares, J. B., Pimentel-Nunes, P., Afonso, L., Rolanda, C., Lopes, P., Roncon-Albuquerque, R. Jr., Goncalves, N., Boal-Carvalho, I., Pardal, F., Lopes, S., Macedo, G., Lara-Santos, L., Henrique, R., Moreira-Dias, L., Goncalves, R., Dinis-Ribeiro, M., and Leite-Moreira, A. F. (2012). Increased hepatic expression of TLR2 and TLR4 in the hepatic inflammation-fibrosis-carcinoma sequence. Innate Immun. (in press).
134. Szabo, G., Velayudham, A., Romics, L. Jr.,andMandrekar,P. (2005).Modulation of non-alcoholic steatohepati-tis by pattern recognition receptors in mice: the role of toll-like receptors 2 and 4. Alcohol. Clin. Exp. Res. 29,140S-145S.
135. Takahashi, K., Asabe, S., Wieland, S., Garaigorta, U., Gastaminza, P., Iso-gawa, M., and Chisari, F. V. (2010). Plasmacytoid dendritic cells sense hepatitis C virus-infected cells, produce interferon, and inhibit infection. Proc. Natl. Acad. Sci. U.S.A. 107, 7431-7436.
136. Takeuchi, O., and Akira, S. (2010). Pattern recognition receptors and inflammation. Cell 140, 805-820.
137. Takii, Y., Nakamura, M., Ito, M., Yokoyama, T., Komori, A., Shimizu-Yoshida, Y., Nakao, R., Kusumoto, K., Nagaoka, S.,Yano,K.,Abiru,S.,Ueki, T., Matsumoto, T., Daikoku, M., Taniguchi, K., Fujioka, H., Migita, K., Yatsuhashi, H., Nakashima, M., Harada, M., and Ishibashi, H. (2005). Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis. Lab. Invest. 85, 908-920.
138. Tazi, K. A., Quioc, J. J., Saada, V., Bezeaud, A., Lebrec, D., and Moreau, R. (2006). Upregulation of TNF-alpha production signaling pathways in monocytes from patients with advanced cirrhosis: possible role of Akt and IRAK-M. J. Hepatol. 45, 280-289.
139. Teratani, T., Tomita, K., Suzuki, T., Oshikawa, T., Yokoyama, H., Shi-mamura, K., Tominaga, S., Hiroi, S., Irie, R., Okada, Y., Kurihara, C., Ebinuma, H., Saito, H., Hokari, R., Sugiyama, K., Kanai, T., Miura, S., and Hibi, T. (2012). A high-cholesterol diet exacerbates liver fibrosis in mice via accumulation of free cholesterol in hepatic stellate cells. Gastroenterology 142, 152-164.
140. Testro, A. G., Gow, P. J., Angus, P. W., Wongseelashote, S., Skinner, N., Markovska, V., and Vis-vanathan, K. (2010). Effects of antibiotics on expression and function of toll-like receptors 2 and 4 on mononuclear cells in patients with advanced cirrhosis. J. Hepatol. 52, 199-205.
141. Thomas, A., Laxton, C., Rodman, J., Myangar, N., Horscroft, N., and Parkinson, T. (2007). Investigating toll-like receptor agonists for potential to treat hepatitis C virus infection. Antimicrob. Agents Chemother. 51,2969-2978.
142. Thompson, A. J., Colledge, D., Rodgers, S., Wilson, R., Revill, P., Desmond, P., Mansell, A., Visvanathan, K., and Locarnini, S. (2009). Stimulation of the interleukin-1 receptor and toll-like receptor 2 inhibits hepatitis B virus replication in hepatoma cell lines in vitro. Antivir. Ther. (Lond.) 14, 797-808.
143. Tsutsui, H., Imamura, M., Fujimoto, J., and Nakanishi, K. (2010). The TLR4/TRIF-mediated activation of NLRP3 inflammasome underlies endotoxin-induced liver injury in mice. Gastroenterol. Res. Pract. 2010, 641-865.
144. Turer, E. E., Tavares, R. M., Mortier, E., Hitotsumatsu, O., Advincula, R., Lee, B., Shifrin, N., Malynn, B. A., and Ma, A. (2008). Homeo-static MyD, 88-dependent signals cause lethal inflammation in the absence of A20. J. Exp. Med. 205, 451-464.
145. Turnbaugh, P. J., Ley, R. E., Mahowald, M. A., Magrini, V., Mardis, E. R., and Gordon, J. I. (2006). An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444,1027-1031.
146. Uesugi, T., Froh, M., Arteel, G. E., Bradford, B. U., and Thur-man, R. G. (2001). Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. Hepatology 34, 101-108.
147. Uesugi, T., Froh, M., Arteel, G. E., Bradford, B. U., Wheeler, M. D., Gabele, E., Isayama, F., and Thurman, R. G. (2002). Role of lipopolysaccharide-binding protein in early alcohol-induced liver injury in mice. J. Immunol. 168,2963-2969.
148. Velayudham, A., Dolganiuc, A., Ellis, M., Petrasek, J., Kodys, K., Mandrekar, P., and Szabo, G. (2009). VSL#3 pro-biotic treatment attenuates fibrosis without changes in steatohepatitis in a diet-induced nonalcoholic steatohepatitis model in mice. Hepatology 49, 989-997.
149. Vincent, I. E., Zannetti, C., Lucifora, J., Norder, H., Protzer, U., Hain-aut, P., Zoulim, F., Tommasino, M., Trepo, C., Hasan, U., and Chemin, I. (2011). Hepatitis B virus impairs TLR9 expression and function in plasmacytoid dendritic cells. PLoS ONE 6, e26315. doi:10.1371/jour-nal.pone.0026315
150. Wang, B., Trippler, M., Pei, R., Lu, M., Broering, R., Gerken, G., and Schlaak, J. F. (2009). Toll-like receptor activated human and murine hepatic stellate cells are potent regulators of hepatitis C virus replication. J. Hepatol. 51, 1037-1045.
151. Watanabe, A., Hashmi, A., Gomes, D. A., Town, T., Badou, A., Flavell, R. A., and Mehal, W Z. (2007). Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9. Hepatology 46, 1509-1518.
152. Weeratna, R. D., Makinen, S. R., McCluskie, M. J., and Davis, H. L. (2005). TLR agonists as vaccine adjuvants: comparison of CpGODN and resiquimod (R-848). Vaccine 23, 5263-5270.
153. Wu, J., Lu, M., Meng, Z., Trippler, M., Broering, R., Szczeponek, A., Krux, F., Dittmer, U., Roggendorf, M., Gerken, G., and Schlaak, J. F. (2007). Toll-like receptor-mediated control of HBV replication by nonparenchy-mal liver cells in mice. Hepatology 46, 1769-1778.
154. Wu, J., Meng, Z., Jiang, M., Zhang, E., Trippler, M., Broering, R., Bucchi, A., Krux, F., Dittmer, U., Yang, D., Roggendorf, M., Gerken, G., Lu, M., and Schlaak, J. F. (2010). Toll-like receptor-induced innate immune responses in non-parenchymal liver cells are cell type-specific. Immunology 129, 363-374.
155. Xu, H., An, H., Hou, J., Han, C., Wang, P., Yu, Y., and Cao, X. (2008a). Phosphatase PTP1B negatively regulates MyD88- and TRIF-dependent proinflammatory cytokine and type I interferon production in TLR-triggered macrophages. Mol. Immunol. 45, 3545-3552.
156. Xu, N., Yao, H. P., Sun, Z., and Chen, Z. (2008b). Toll-like receptor 7 and 9 expression in peripheral blood mononuclear cells from patients with chronic hepatitis B and related hepatocellular carcinoma. Acta Pharmacol. Sin. 29, 239-244.
157. Xu, J., Lai, K. K., Verlinsky, A., Lugea, A., French, S. W., Cooper, M. P., Ji, C., and Tsukamoto, H. (2011). Syn-ergistic steatohepatitis by moderate obesity and alcohol in mice despite increased adiponectin and p-AMPK. J. Hepatol. 55, 673-682.
158. Yamamoto, M., and Takeda, K. (2010). Current views of toll-like receptor signaling pathways. Gastroenterol. Res. Pract. 2010, 240-365.
159. Yan, A. W., Fouts, D. E., Brandl, J., Stärkel, P., Torralba, M., Schott, E., Tsukamoto, H., Nelson, K. E., Brenner, D. A., and Schnabl, B. (2011). Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology 53, 96-105.
160. Yan, X., Lin, Z., Chen, F., Zhao, X., Chen, H., Ning, Y., and Chen, Y G. (2009). Human BAMBI cooperates with Smad7 to inhibit transforming growth factor-beta signaling. J. Biol. Chem. 284,30097-30104.
161. Yin, M., Bradford, B. U., Wheeler, M. D., Uesugi, T., Froh, M., Goyert, S. M., and Thurman, R. G. (2001). Reduced early alcohol-induced liver injury in CD14-deficient mice. J. Immunol. 166,4737-4742.
162. Yin, S., and Gao, B. (2010). Toll-like receptor 3 in liver diseases. Gastroen-terol Res. Pract. 2010, 6.
163. Zanoni, I., Ostuni, R., Marek, L. R., Barresi, S., Barbalat, R., Barton, G. M., Granucci, F., and Kagan, J. C. (2011). CD14 controls the LPS-induced endocytosis of toll-like receptor 4. Cell 147, 868-880.
164. Zhang, W., Gu, Y., Chen, Y., Deng, H., Chen, L., Chen, S., Zhang, G., and Gao, Z. (2010a). Intestinal flora imbalance results in altered bacterial translocation and liver function in rats with experimental cirrhosis. Eur. J. Gastroenterol. Hepatol. 22, 1481-1486.
165. Zhang, Y., Lian, J. Q., Huang, C. X., Wang, J. P., Wei, X., Nan, X. P., Yu, H. T., Jiang, L. L.,Wang, X. Q., Zhuang, Y.,Li,X.H.,Li,Y.,Wang,P.Z.,Robek, M. D., and Bai, X. E (2010b). Over-expression of toll-like receptor 2/4 on monocytes modulates the activities of CD, 4(+)CD, 25(+) regulatory T cells in chronic hepatitis B virus infection. Virology 397, 34-42.
166. Zhang, Y L, Guo, Y J., Bin, L., and Sun, S. H. (2009). Hepatitis C virus single-stranded RNA induces innate immunity via toll-like receptor 7. J. Hepatol. 51,29-38.
167. Zhou, J., Huang, Y., Tian, D., Xu, D., Chen, M., and Wu, H. (2009). Expression of toll-like receptor 9 in peripheral blood mononuclear cells from patients with different hepatitis B and C viral loads. J. Huazhong Univ. Sci. Technol. Med. Sci. 29, 313-317.
168. Zhu, Q., Zou, L., Jagavelu, K., Simonetto, D. A., Huebert, R. C., Jiang, Z. D., Dupont, H. L., and Shah, V. H. (2012). Intestinal decontamination inhibits TLR4 dependent fibronectin mediated crosstalk between stellate cells and endothe-lial cells in liver fibrosis in mice. J. Hepatol. 56, 893-899.