Table of Contents Author Guidelines Submit a Manuscript
Gastroenterology Research and Practice
Volume 2010 (2010), Article ID 367694, 10 pages
http://dx.doi.org/10.1155/2010/367694
Review Article

NF-κB, JNK, and TLR Signaling Pathways in Hepatocarcinogenesis

Department of Gastroenterology, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan

Received 1 May 2010; Accepted 22 October 2010

Academic Editor: Timothy R. Billiar

Copyright © 2010 Shin Maeda. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. F. X. Bosch, J. Ribes, M. Díaz, and R. Cléries, “Primary liver cancer: worldwide incidence and trends,” Gastroenterology, vol. 127, pp. S5–S16, 2004. View at Publisher · View at Google Scholar · View at Scopus
  2. K. Koike, T. Tsutsumi, H. Fujie, Y. Shintani, and K. Moriya, “Molecular mechanism of viral hepatocarcinogenesis,” Oncology, vol. 62, no. 1, pp. 29–37, 2002. View at Publisher · View at Google Scholar · View at Scopus
  3. N. Fausto, “Mouse liver tumorigenesis: models, mechanisms, and relevance to human disease,” Seminars in Liver Disease, vol. 19, no. 3, pp. 243–252, 1999. View at Google Scholar · View at Scopus
  4. T. Sakurai, S. Maeda, L. Chang, and M. Karin, “Loss of hepatic NF-κB activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 28, pp. 10544–10551, 2006. View at Publisher · View at Google Scholar · View at Scopus
  5. N. Kato, H. Yoshida, S. Kioko Ono-Nita et al., “Activation of intracellular signaling by hepatitis B and C viruses: C-viral core is the most potent signal inducer,” Hepatology, vol. 32, no. 2, pp. 405–412, 2000. View at Google Scholar · View at Scopus
  6. S. H. Caldwell and D. M. Crespo, “The spectrum expanded: cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver disease,” Journal of Hepatology, vol. 40, no. 4, pp. 578–584, 2004. View at Publisher · View at Google Scholar · View at Scopus
  7. E. E. Calle and R. Kaaks, “Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms,” Nature Reviews Cancer, vol. 4, no. 8, pp. 579–591, 2004. View at Google Scholar · View at Scopus
  8. E. J. Park, J. H. Lee, G.-Y. Yu et al., “Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression,” Cell, vol. 140, no. 2, pp. 197–208, 2010. View at Publisher · View at Google Scholar
  9. E. Dejardin, N. M. Droin, M. Delhase et al., “The lymphotoxin-β receptor induces different patterns of gene expression via two NF-κB pathways,” Immunity, vol. 17, no. 4, pp. 525–535, 2002. View at Publisher · View at Google Scholar · View at Scopus
  10. S. Ghosh and M. Karin, “Missing pieces in the NF-κB puzzle,” Cell, vol. 109, no. 2, pp. S81–S96, 2002. View at Publisher · View at Google Scholar · View at Scopus
  11. F. Aslund and J. Beckwith, “The thioredoxin superfamily: redundancy, specificity, and gray-area genomics,” Journal of Bacteriology, vol. 181, no. 5, pp. 1375–1379, 1999. View at Google Scholar · View at Scopus
  12. M. Karin, Y. Cao, F. R. Greten, and Z.-W. Li, “NF-κB in cancer: from innocent bystander to major culprit,” Nature Reviews Cancer, vol. 2, no. 4, pp. 301–310, 2002. View at Google Scholar · View at Scopus
  13. N. Kabrun and P. J. Enrietto, “The Rel family of proteins in oncogenesis and differentiation,” Seminars in Cancer Biology, vol. 5, no. 2, pp. 103–112, 1994. View at Google Scholar · View at Scopus
  14. D. Hanahan and R. A. Weinberg, “The hallmarks of cancer,” Cell, vol. 100, no. 1, pp. 57–70, 2000. View at Google Scholar · View at Scopus
  15. P. W. Szlosarek and F. R. Balkwill, “Tumour necrosis factor α: a potential target for the therapy of solid tumours,” The Lancet Oncology, vol. 4, no. 9, pp. 565–573, 2003. View at Publisher · View at Google Scholar · View at Scopus
  16. D. C. Guttridge, C. Albanese, J. Y. Reuther, R. G. Pestell, and A. S. Baldwin Jr., “NF-κB controls cell growth and differentiation through transcriptional regulation of cyclin D1,” Molecular and Cellular Biology, vol. 19, no. 8, pp. 5785–5799, 1999. View at Google Scholar · View at Scopus
  17. K. S. Koch, S. Maeda, G. He, M. Karin, and H. L. Leffert, “Targeted deletion of hepatocyte Ikkβ confers growth advantages,” Biochemical and Biophysical Research Communications, vol. 380, no. 2, pp. 349–354, 2009. View at Publisher · View at Google Scholar · View at Scopus
  18. M. Karin and A. Lin, “NF-κB at the crossroads of life and death,” Nature Immunology, vol. 3, no. 3, pp. 221–227, 2002. View at Publisher · View at Google Scholar · View at Scopus
  19. S. Müerköster, A. Arlt, B. Sipos et al., “Increased expression of the E3-ubiquitin ligase receptor subunit βTRCP1 relates to constitutive nuclear factor-κB activation and chemoresistance in pancreatic carcinoma cells,” Cancer Research, vol. 65, no. 4, pp. 1316–1324, 2005. View at Publisher · View at Google Scholar · View at Scopus
  20. Q. Cheng, H. H. Lee, Y. Li, T. P. Parks, and G. Cheng, “Upregulation of Bcl-x an Bfl-1 as a potential mechanism of chemoresistance, which can be overcome by NF-κB inhibition,” Oncogene, vol. 19, no. 42, pp. 4936–4940, 2000. View at Google Scholar · View at Scopus
  21. A. B. Kunnumakkara, S. Guha, S. Krishnan, P. Diagaradjane, J. Gelovani, and B. B. Aggarwal, “Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-κB-regulated gene products,” Cancer Research, vol. 67, no. 8, pp. 3853–3861, 2007. View at Publisher · View at Google Scholar · View at Scopus
  22. K. Sakamoto, S. Maeda, Y. Hikiba et al., “Constitutive NF-κB activation in colorectal carcinoma plays a key role in angiogenesis, promoting tumor growth,” Clinical Cancer Research, vol. 15, no. 7, pp. 2248–2258, 2009. View at Publisher · View at Google Scholar · View at Scopus
  23. M. Egeblad and Z. Werb, “New functions for the matrix metalloproteinases in cancer progression,” Nature Reviews Cancer, vol. 2, no. 3, pp. 161–174, 2002. View at Google Scholar · View at Scopus
  24. S. Maeda, Y. Hikiba, K. Sakamoto et al., “Ikappa B kinaseβ/nuclear factor-κB activation controls the development of liver metastasis by way of interleukin-6 expression,” Hepatology, vol. 50, no. 6, pp. 1851–1860, 2009. View at Publisher · View at Google Scholar
  25. D.-I. Tai, S.-L. Tsai, Y.-H. Chang et al., “Constitutive activation of nuclear factor κB in hepatocellular carcinoma,” Cancer, vol. 89, no. 11, pp. 2274–2281, 2000. View at Publisher · View at Google Scholar · View at Scopus
  26. R. Jiang, Y. Xia, J. Li et al., “High expression levels of IKKα and IKKβ are necessary for the malignant properties of liver cancer,” International Journal of Cancer, vol. 126, no. 5, pp. 1263–1274, 2010. View at Publisher · View at Google Scholar
  27. Z.-W. Li, W. Chu, Y. Hu et al., “The IKKβ subunit of IκB kinase (IKK) is essential for nuclear factor κB activation and prevention of apoptosis,” Journal of Experimental Medicine, vol. 189, no. 11, pp. 1839–1845, 1999. View at Publisher · View at Google Scholar · View at Scopus
  28. S. Maeda, L. Chang, Z.-W. Li, J.-L. Luo, H. Leffert, and M. Karin, “IKKβ is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFα,” Immunity, vol. 19, no. 5, pp. 725–737, 2003. View at Publisher · View at Google Scholar · View at Scopus
  29. S. Maeda, H. Kamata, J.-L. Luo, H. Leffert, and M. Karin, “IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis,” Cell, vol. 121, no. 7, pp. 977–990, 2005. View at Publisher · View at Google Scholar · View at Scopus
  30. G. Tang, Y. Minemoto, B. Dibling et al., “Inhibition of JNK activation through NF-κB target genes,” Nature, vol. 414, no. 6861, pp. 313–317, 2001. View at Publisher · View at Google Scholar · View at Scopus
  31. N. Fausto, “Liver regeneration,” Journal of Hepatology, vol. 32, no. 1, pp. 19–31, 2000. View at Google Scholar · View at Scopus
  32. W. E. Naugler, T. Sakurai, S. Kim et al., “Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production,” Science, vol. 317, no. 5834, pp. 121–124, 2007. View at Publisher · View at Google Scholar · View at Scopus
  33. G. He, G.-Y. Yu, V. Temkin et al., “Hepatocyte IKKβ/NF-κB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation,” Cancer Cell, vol. 17, no. 3, pp. 286–297, 2010. View at Publisher · View at Google Scholar
  34. T. Luedde, N. Beraza, V. Kotsikoris et al., “Deletion of NEMO/IKKγ in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma,” Cancer Cell, vol. 11, no. 2, pp. 119–132, 2007. View at Publisher · View at Google Scholar · View at Scopus
  35. T. Zhao, L. Yang, Q. Sun et al., “The NEMO adaptor bridges the nuclear factor-κB and interferon regulatory factor signaling pathways,” Nature Immunology, vol. 8, no. 6, pp. 592–600, 2007. View at Publisher · View at Google Scholar · View at Scopus
  36. Y. Hayakawa, S. Maeda, H. Nakagawa et al., “Effectiveness of IκB kinase inhibitors in murine colitis-associated tumorigenesis,” Journal of Gastroenterology, vol. 44, no. 9, pp. 935–943, 2009. View at Publisher · View at Google Scholar · View at Scopus
  37. M. Karin, Y. Yamamoto, and Q. M. Wang, “The IKK NF-κB system: a treasure trove for drug development,” Nature Reviews Drug Discovery, vol. 3, no. 1, pp. 17–26, 2004. View at Google Scholar · View at Scopus
  38. B. Dérijard, M. Hibi, I.-H. Wu et al., “JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain,” Cell, vol. 76, no. 6, pp. 1025–1037, 1994. View at Publisher · View at Google Scholar · View at Scopus
  39. T. Kallunki, B. Su, I. Tsigelny et al., “JNK2 contains a specificity-determining region responsible for efficient c-Jun binding and phosphorylation,” Genes and Development, vol. 8, no. 24, pp. 2996–3007, 1994. View at Google Scholar · View at Scopus
  40. A. A. Mohit, J. H. Martin, and C. A. Miller, “p49(3F12) kinase: a novel MAP kinase expressed in a subset of neurons in the human nervous system,” Neuron, vol. 14, no. 1, pp. 67–78, 1995. View at Google Scholar · View at Scopus
  41. X. Wang, A. Destrument, and C. Tournier, “Physiological roles of MKK4 and MKK7: insights from animal models,” Biochimica et Biophysica Acta, vol. 1773, no. 8, pp. 1349–1357, 2007. View at Publisher · View at Google Scholar · View at Scopus
  42. S. Gupta, T. Barrett, A. J. Whitmarsh et al., “Selective interaction of JNK protein kinase isoforms with transcription factors,” The EMBO Journal, vol. 15, no. 11, pp. 2760–2770, 1996. View at Google Scholar · View at Scopus
  43. E. Shaulian and M. Karin, “AP-1 as a regulator of cell life and death,” Nature Cell Biology, vol. 4, no. 5, pp. E131–E136, 2002. View at Publisher · View at Google Scholar · View at Scopus
  44. C. R. Weston and R. J. Davis, “The JNK signal transduction pathway,” Current Opinion in Genetics and Development, vol. 12, no. 1, pp. 14–21, 2002. View at Publisher · View at Google Scholar · View at Scopus
  45. K. Sabapathy, Y. Hu, T. Kallunki et al., “JNK2 is required for efficient T-cell activation and apoptosis but not for normal lymphocyte development,” Current Biology, vol. 9, no. 3, pp. 116–125, 1999. View at Publisher · View at Google Scholar · View at Scopus
  46. K. Sabapathy and E. F. Wagner, “JNK2: a negative regulator of cellular proliferation,” Cell Cycle, vol. 3, no. 12, pp. 1520–1523, 2004. View at Google Scholar · View at Scopus
  47. C.-Y. Kuan, D. D. Yang, D. R. Samanta Roy, R. J. Davis, P. Rakic, and R. A. Flavell, “The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development,” Neuron, vol. 22, no. 4, pp. 667–676, 1999. View at Publisher · View at Google Scholar · View at Scopus
  48. J. Hirosumi, G. Tuncman, L. Chang et al., “A central, role for JNK in obesity and insulin resistance,” Nature, vol. 420, no. 6913, pp. 333–336, 2002. View at Publisher · View at Google Scholar · View at Scopus
  49. C. Tournier, P. Hess, D. D. Yang et al., “Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway,” Science, vol. 288, no. 5467, pp. 870–874, 2000. View at Publisher · View at Google Scholar · View at Scopus
  50. N. Hanawa, M. Shinohara, B. Saberi, W. A. Gaarde, D. Han, and N. Kaplowitz, “Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury,” Journal of Biological Chemistry, vol. 283, no. 20, pp. 13565–13577, 2008. View at Publisher · View at Google Scholar · View at Scopus
  51. H. Nakagawa, S. Maeda, Y. Hikiba et al., “Deletion of apoptosis signal-regulating kinase 1 attenuates acetaminophen-induced liver injury by inhibiting c-Jun N-terminal kinase activation,” Gastroenterology, vol. 135, no. 4, pp. 1311–1321, 2008. View at Publisher · View at Google Scholar · View at Scopus
  52. M. Das, G. Sabio, F. Jiang, M. Rincón, R. A. Flavell, and R. J. Davis, “Induction of hepatitis by JNK-mediated expression of TNF-α,” Cell, vol. 136, no. 2, pp. 249–260, 2009. View at Publisher · View at Google Scholar · View at Scopus
  53. V. T. Samuel, Z.-X. Liu, X. Qu et al., “Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease,” Journal of Biological Chemistry, vol. 279, no. 31, pp. 32345–32353, 2004. View at Publisher · View at Google Scholar · View at Scopus
  54. Y. Kodama, T. Kisseleva, K. Iwaisako et al., “c-Jun N-terminal kinase-1 from hematopoietic cells mediates progression from hepatic steatosis to steatohepatitis and fibrosis in mice,” Gastroenterology, vol. 137, no. 4, pp. 1467–1477, 2009. View at Publisher · View at Google Scholar · View at Scopus
  55. C. Tong, Z. Yin, Z. Song et al., “c-Jun NH2-terminal kinase 1 plays a critical role in intestinal homeostasis and tumor suppression,” American Journal of Pathology, vol. 171, no. 1, pp. 297–303, 2007. View at Publisher · View at Google Scholar · View at Scopus
  56. W. Shibata, S. Maeda, Y. Hikiba et al., “c-Jun NH2-terminal kinase 1 is a critical regulator for the development of gastric cancer in mice,” Cancer Research, vol. 68, no. 13, pp. 5031–5039, 2008. View at Publisher · View at Google Scholar · View at Scopus
  57. A. Minden, A. Lin, M. McMahon et al., “Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK,” Science, vol. 266, no. 5191, pp. 1719–1723, 1994. View at Google Scholar · View at Scopus
  58. G. J. Clark, J. K. Westwick, and C. J. Der, “p120 GAP modulates Ras activation of jun kinases and transformation,” Journal of Biological Chemistry, vol. 272, no. 3, pp. 1677–1681, 1997. View at Publisher · View at Google Scholar · View at Scopus
  59. L. Hui, K. Zatloukal, H. Scheuch, E. Stepniak, and E. F. Wagner, “Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation,” Journal of Clinical Investigation, vol. 118, no. 12, pp. 3943–3953, 2008. View at Publisher · View at Google Scholar · View at Scopus
  60. F. Bost, R. McKay, N. Dean, and D. Mercola, “The JUN kinase/stress-activated protein kinase pathway is required for epidermal growth factor stimulation of growth of human A549 lung carcinoma cells,” Journal of Biological Chemistry, vol. 272, no. 52, pp. 33422–33429, 1997. View at Publisher · View at Google Scholar · View at Scopus
  61. C. R. Weston, A. Wong, J. P. Hall, M. E. P. Goad, R. A. Flavell, and R. J. Davis, “The c-Jun NH2-terminal kinase is essential for epidermal growth factor expression during epidermal morphogenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 39, pp. 14114–14119, 2004. View at Publisher · View at Google Scholar · View at Scopus
  62. M. Guma, J. Rius, K. X. Duong-Polk, G. G. Haddad, J. D. Lindsey, and M. Karin, “Genetic and pharmacological inhibition of JNK ameliorates hypoxia-induced retinopathy through interference with VEGF expression,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 21, pp. 8760–8765, 2009. View at Publisher · View at Google Scholar · View at Scopus
  63. R. M. Strieter, P. J. Polverini, D. A. Arenberg et al., “Role of C-X-C chemokines as regulators of angiogenesis in lung cancer,” Journal of Leukocyte Biology, vol. 57, no. 5, pp. 752–762, 1995. View at Google Scholar · View at Scopus
  64. S. Yoshida, M. Ono, T. Shono et al., “Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis,” Molecular and Cellular Biology, vol. 17, no. 7, pp. 4015–4023, 1997. View at Google Scholar · View at Scopus
  65. Q. Chang, Y. Zhang, K. J. Beezhold et al., “Sustained JNK1 activation is associated with altered histone H3 methylations in human liver cancer,” Journal of Hepatology, vol. 50, no. 2, pp. 323–333, 2009. View at Publisher · View at Google Scholar · View at Scopus
  66. C. Tarn, S. Lee, Y. Hu, C. Ashendel, and O. M. Andrisani, “Hepatitis B virus X protein differentially activates RAS-RAF-MAPK and JNK pathways in X-transforming versus non-transforming AML12 hepatocytes,” Journal of Biological Chemistry, vol. 276, no. 37, pp. 34671–34680, 2001. View at Publisher · View at Google Scholar · View at Scopus
  67. M. Hibi, A. Lin, T. Smeal, A. Minden, and M. Karin, “Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain,” Genes and Development, vol. 7, no. 11, pp. 2135–2148, 1993. View at Google Scholar · View at Scopus
  68. R. Eferl, R. Ricci, L. Kenner et al., “Liver tumor development: c-Jun antagonizes the proapoptotic activity of p53,” Cell, vol. 112, no. 2, pp. 181–192, 2003. View at Publisher · View at Google Scholar · View at Scopus
  69. P. Angel and M. Karin, “The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation,” Biochimica et Biophysica Acta, vol. 1072, no. 2-3, pp. 129–157, 1991. View at Google Scholar · View at Scopus
  70. A. Matsuzawa and H. Ichijo, “Redox control of cell fate by MAP kinase: physiological roles of ASK1-MAP kinase pathway in stress signaling,” Biochimica et Biophysica Acta, vol. 1780, no. 11, pp. 1325–1336, 2008. View at Publisher · View at Google Scholar · View at Scopus
  71. F. Chen, K. Beezhold, and V. Castranova, “JNK1, a potential therapeutic target for hepatocellular carcinoma,” Biochimica et Biophysica Acta, vol. 1796, no. 2, pp. 242–251, 2009. View at Publisher · View at Google Scholar · View at Scopus
  72. H. Kamata, S.-I. Honda, S. Maeda, L. Chang, H. Hirata, and M. Karin, “Reactive oxygen species promote TNFα-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases,” Cell, vol. 120, no. 5, pp. 649–661, 2005. View at Publisher · View at Google Scholar · View at Scopus
  73. M. Okuda, K. Li, M. R. Beard et al., “Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein,” Gastroenterology, vol. 122, no. 2, pp. 366–375, 2002. View at Google Scholar · View at Scopus
  74. S. Inokuchi, T. Aoyama, K. Miura et al., “Disruption of TAK1 in hepatocytes causes hepatic injury, inflammation, fibrosis, and carcinogenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 2, pp. 844–849, 2010. View at Publisher · View at Google Scholar
  75. M. Takamura, Y. Matsuda, S. Yamagiwa et al., “An inhibitor of c-Jun NH2-terminal kinase, SP600125, protects mice from d-galactosamine/lipopolysaccharide-induced hepatic failure by modulating BH3-only proteins,” Life Sciences, vol. 80, no. 14, pp. 1335–1344, 2007. View at Publisher · View at Google Scholar · View at Scopus
  76. O. Takeuchi and S. Akira, “Toll-like receptors; their physiological role and signal transduction system,” International Immunopharmacology, vol. 1, no. 4, pp. 625–635, 2001. View at Publisher · View at Google Scholar · View at Scopus
  77. L. A. J. O'Neill and A. G. Bowie, “The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling,” Nature Reviews Immunology, vol. 7, no. 5, pp. 353–364, 2007. View at Publisher · View at Google Scholar · View at Scopus
  78. S. Akira, S. Uematsu, and O. Takeuchi, “Pathogen recognition and innate immunity,” Cell, vol. 124, no. 4, pp. 783–801, 2006. View at Publisher · View at Google Scholar · View at Scopus
  79. E. Seki and D. A. Brenner, “Toll-like receptors and adaptor molecules in liver disease: update,” Hepatology, vol. 48, no. 1, pp. 322–335, 2008. View at Publisher · View at Google Scholar · View at Scopus
  80. M. Isogawa, M. D. Robek, Y. Furuichi, and F. V. Chisari, “Toll-like receptor signaling inhibits hepatitis B virus replication in vivo,” Journal of Virology, vol. 79, no. 11, pp. 7269–7272, 2005. View at Publisher · View at Google Scholar · View at Scopus
  81. K. Visvanathan, N. A. Skinner, A. J. V. Thompson et al., “Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein,” Hepatology, vol. 45, no. 1, pp. 102–110, 2007. View at Publisher · View at Google Scholar · View at Scopus
  82. A. Dolganiuc, S. Oak, K. Kodys et al., “Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation,” Gastroenterology, vol. 127, no. 5, pp. 1513–1524, 2004. View at Publisher · View at Google Scholar · View at Scopus
  83. K. Li, E. Foy, J. C. Ferreon et al., “Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 8, pp. 2992–2997, 2005. View at Publisher · View at Google Scholar · View at Scopus
  84. I. Bjarnason, K. Ward, and T. J. Peters, “The leaky gut of alcoholism: possible route of entry for toxic compounds,” The Lancet, vol. 1, no. 8370, pp. 179–182, 1984. View at Google Scholar · View at Scopus
  85. Y. Adachi, L. E. Moore, B. U. Bradford, W. Gao, and R. G. Thurman, “Antibiotics prevent liver injury in rats following long-term exposure to ethanol,” Gastroenterology, vol. 108, no. 1, pp. 218–224, 1995. View at Publisher · View at Google Scholar · View at Scopus
  86. T. Uesugi, M. Froh, G. E. Arteel, B. U. Bradford, and R. G. Thurman, “Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice,” Hepatology, vol. 34, no. 1, pp. 101–108, 2001. View at Publisher · View at Google Scholar · View at Scopus
  87. S. Q. Yang, H. Z. Lin, M. D. Lane, M. Clemens, and A. M. Diehl, “Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 6, pp. 2557–2562, 1997. View at Publisher · View at Google Scholar · View at Scopus
  88. C. A. Rivera, P. Adegboyega, N. van Rooijen, A. Tagalicud, M. Allman, and M. Wallace, “Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis,” Journal of Hepatology, vol. 47, no. 4, pp. 571–579, 2007. View at Publisher · View at Google Scholar · View at Scopus
  89. R. F. Schwabe, E. Seki, and D. A. Brenner, “Toll-Like receptor signaling in the liver,” Gastroenterology, vol. 130, no. 6, pp. 1886–1900, 2006. View at Publisher · View at Google Scholar · View at Scopus
  90. T. Matsumura, T. Degawa, T. Takii et al., “TRAF6-NF-κB pathway is essential for interleukin-1-induced TLR2 expression and its functional response to TLR2 ligand in murine hepatocytes,” Immunology, vol. 109, no. 1, pp. 127–136, 2003. View at Publisher · View at Google Scholar · View at Scopus
  91. S. Liu, D. J. Gallo, A. M. Green et al., “Role of toll-like receptors in changes in gene expression and NF-κB activation in mouse hepatocytes stimulated with lipopolysaccharide,” Infection and Immunity, vol. 70, no. 7, pp. 3433–3442, 2002. View at Publisher · View at Google Scholar · View at Scopus
  92. T. Matsumura, A. Ito, T. Takii, H. Hayashi, and K. Onozaki, “Endotoxin and cytokine regulation of toll-like receptor (TLR) 2 and TLR4 gene expression in murine liver and hepatocytes,” Journal of Interferon and Cytokine Research, vol. 20, no. 10, pp. 915–921, 2000. View at Publisher · View at Google Scholar · View at Scopus
  93. S. Maeda and M. Omata, “Inflammation and cancer: role of nuclear factor-kappaB activation,” Cancer Science, vol. 99, no. 5, pp. 836–842, 2008. View at Publisher · View at Google Scholar · View at Scopus