Role of nuclear factor κB in liver health and disease

Clinical Science

Volumn 118, Issue 12, 2010, Pages 691-705

  Robinson, Stuart M ^a   Mann, Derek A ^a  

^a NEWCASTLE UNIVERSITY   (United Kingdom)

Author keywords

Fibrosis; Hepatocellular carcinoma; Ischaemia reperfusion injury; Non alcoholic fatty liver disease (NAFLD); Nuclear factor B (NF B); Regeneration

Indexed keywords

I KAPPA B KINASE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN;

CHOLESTASIS; DNA DAMAGE; HEPATITIS; HOMEOSTASIS; HUMAN; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; LIVER DISEASE; LIVER FIBROSIS; LIVER ISCHEMIA; LIVER REGENERATION; NONALCOHOLIC FATTY LIVER; PATHOGENESIS; PRIORITY JOURNAL; REPERFUSION INJURY; REVIEW; SIGNAL TRANSDUCTION; VIRUS HEPATITIS; LIVER; PATHOPHYSIOLOGY; PHYSIOLOGY;

DNA DAMAGE; HOMEOSTASIS; HUMANS; LIVER; LIVER DISEASES; NF-KAPPA B; SIGNAL TRANSDUCTION;

EID: 77954062579     PISSN: 01435221     EISSN: None     Source Type: Journal    
DOI: 10.1042/CS20090549     Document Type: Review

References (114)

1. Sen, R. and Baltimore, D. (1986) Inducibility of κ immunoglobulin enhancer-binding protein NF-κB by a posttranslational mechanism. Cell 47, 921-928
2. Ahn, K. S. and Aggarwal, B. B. (2005) Transcription factor NF-κB: a sensor for smoke and stress signals. Ann. N.Y. Acad. Sci. 1056, 218-233
3. Hacker, H. and Karin, M. (2006) Regulation and function of IKK and IKK-related kinases. Sci. STKE 2006, re13
4. Bonizzi, G. and Karin, M. (2004) The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 25, 280-288
5. DiDonato, J. A., Hayakawa, M., Rothwarf, D. M., Zandi, E. and Karin, M. (1997) A cytokine-responsive IκB kinase that activates the transcription factor NF-κB. Nature 388, 548-554
6. Chen, Z., Hagler, J., Palombella, V. J., Melandri, F., Scherer, D., Ballard, D. and Maniatis, T. (1995) Signal-induced site-specific phosphorylation targets IκBα to the ubiquitin-proteasome pathway. Genes Dev. 9, 1586-1597
7. Zhong, H., Voll, R. E. and Ghosh, S. (1998) Phosphorylation of NF-κB p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300. Mol. Cell 1, 661-671 (Pubitemid 128379244)
8. Naumann, M. and Scheidereit, C. (1994) Activation of NF-κB in vivo is regulated by multiple phosphorylations. EMBO J. 13, 4597-4607
9. Wang, D. and Baldwin, Jr, A. S. (1998) Activation of nuclear factor-κB-dependent transcription by tumor necrosis factor-α is mediated through phosphorylation of RelA/p65 on serine 529. J. Biol. Chem. 273, 29411-29416
10. Sakurai, H., Suzuki, S., Kawasaki, N., Nakano, H., Okazaki, T., Chino, A., Doi, T. and Saiki, I. (2003) Tumor necrosis factor-α-induced IKK phosphorylation of NF-κB p65 on serine 536 is mediated through the TRAF2, TRAF5, and TAK1 signaling pathway. J. Biol. Chem. 278, 36916-36923
11. ras and protein kinase Czeta in primary endothelial cells. J. Biol. Chem. 274, 13594-13603
12. Hayden, M. S. and Ghosh, S. (2004) Signaling to NF-κB. Genes Dev. 18, 2195-2224
13. Beg, A. A., Sha, W. C., Bronson, R. T., Ghosh, S. and Baltimore, D. (1995) Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB. Nature 376, 167-170
14. Li, Q., Van Antwerp, D., Mercurio, F., Lee, K. F. and Verma, I. M. (1999) Severe liver degeneration in mice lacking the IκB kinase 2 gene. Science 284, 321-325
15. Li, Z. W., Chu, W., Hu, Y., Delhase, M., Deerinck, T., Ellisman, M., Johnson, R. and Karin, M. (1999) The IKKβ subunit of IκB kinase (IKK) is essential for nuclear factor κB activation and prevention of apoptosis. J. Exp. Med. 189, 1839-1845
16. Doi, T. S., Marino, M. W., Takahashi, T., Yoshida, T., Sakakura, T., Old, L. J. and Obata, Y. (1999) Absence of tumor necrosis factor rescues RelA-deficient mice from embryonic lethality. Proc. Natl. Acad. Sci. U.S.A. 96, 2994-2999
17. Scheidereit, C. (2006) IκB kinase complexes: gateways to NF-κB activation and transcription. Oncogene 25, 6685-6705
18. Gilmore, T. D. (2006) Introduction to NF-κB: players, pathways, perspectives. Oncogene 25, 6680-6684
19. Hu, Y., Baud, V., Delhase, M., Zhang, P., Deerinck, T., Ellisman, M., Johnson, R. and Karin, M. (1999) Abnormal morphogenesis but intact IKK activation in mice lacking the IKKα subunit of IκB kinase. Science 284, 316-320
20. Janssens, S. and Tschopp, J. (2006) Signals from within: the DNA-damage-induced NF-κB response. Cell Death Differ. 13, 773-784
21. Piret, B., Schoonbroodt, S. and Piette, J. (1999) The ATM protein is required for sustained activation of NF-κB following DNA damage. Oncogene 18, 2261-2271
22. Li, N., Banin, S., Ouyang, H., Li, G. C., Courtois, G., Shiloh, Y., Karin, M. and Rotman, G. (2001) ATM is required for IκB kinase (IKK) activation in response to DNA double strand breaks. J. Biol. Chem. 276, 8898-8903
23. Habraken, Y. and Piette, J. (2006) NF-κB activation by double-strand breaks. Biochem. Pharmacol. 72, 1132-1141
24. Janssens, S., Tinel, A., Lippens, S. and Tschopp, J. (2005) PIDD mediates NF-κB activation in response to DNA damage. Cell 123, 1079-1092
25. Verma, U. N., Yamamoto, Y., Prajapati, S. and Gaynor, R. B. (2004) Nuclear role of I κB kinase-γ/NF-κB essential modulator (IKKγ/NEMO) in NF-κB-dependent gene expression. J. Biol. Chem. 279, 3509-3515
26. Wu, Z. H., Shi, Y., Tibbetts, R. S. and Miyamoto, S. (2006) Molecular linkage between the kinase ATM and NF-κB signaling in response to genotoxic stimuli. Science 311, 1141-1146
27. Vauthey, J. N., Pawlik, T. M., Ribero, D., Wu, T. T., Zorzi, D., Hoff, P. M., Xiong, H. Q., Eng, C., Lauwers, G. Y., Mino-Kenudson, M. et al. (2006) Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J. Clin. Oncol. 24, 2065-2072
28. Schoemaker, M. H., Gommans, W. M., Conde de la Rosa, L., Homan, M., Klok, P., Trautwein, C., van Goor, H., Poelstra, K., Haisma, H. J., Jansen, P. L. and Moshage, H. (2003) Resistance of rat hepatocytes against bile acid-induced apoptosis in cholestatic liver injury is due to nuclear factor-κB activation. J. Hepatol. 39, 153-161
29. Miyoshi, H., Rust, C., Guicciardi, M. E. and Gores, G. J. (2001) NF-κB is activated in cholestasis and functions to reduce liver injury. Am. J. Pathol. 158, 967-975
30. Gehring, S., Dickson, E. M., San Martin, M. E., van Rooijen, N., Papa, E. F., Harty, M. W., Tracy, Jr, T. F. and Gregory, S. H. (2006) Kupffer cells abrogate cholestatic liver injury in mice. Gastroenterology 130, 810-822 (Pubitemid 43374530)
31. Yu, H. and Wu, S. D. (2008) Activation of TLR-4 and liver injury via NF-κB in rat with acute cholangitis. Hepatobiliary Pancreat. Dis. Int. 7, 185-191
32. Luedde, T., Heinrichsdorff, J., de Lorenzi, R., De Vos, R., Roskams, T. and Pasparakis, M. (2008) IKK1 and IKK2 cooperate to maintain bile duct integrity in the liver. Proc. Natl. Acad. Sci. U.S.A. 105, 9733-9738
33. Wang, Y. D., Chen, W. D., Wang, M., Yu, D., Forman, B. M. and Huang, W. (2008) Farnesoid X receptor antagonizes nuclear factor κB in hepatic inflammatory response. Hepatology 48, 1632-1643
34. Neuschwander-Tetri, B. A. and Caldwell, S. H. (2003) Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 37, 1202-1219
35. Falck-Ytter, Y., Younossi, Z. M., Marchesini, G. and McCullough, A. J. (2001) Clinical features and natural history of nonalcoholic steatosis syndromes. Semin. Liver Dis. 21, 17-26
36. Clark, J. M. and Diehl, A. M. (2002) Hepatic steatosis and type 2 diabetes mellitus. Curr. Diabetes Rep. 2, 210-215
37. Marchesini, G., Bugianesi, E., Forlani, G., Cerrelli, F., Lenzi, M., Manini, R., Natale, S., Vanni, E., Villanova, N., Melchionda, N. and Rizzetto, M. (2003) Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 37, 917-923
38. Day, C. P. (2006) Non-alcoholic fatty liver disease: current concepts and management strategies. Clin. Med. 6, 19-25
39. Day, C. P. and James, O. F. (1998) Steatohepatitis: a tale of two "hits"? Gastroenterology 114, 842-845
40. Diehl, A. M., Li, Z. P., Lin, H. Z. and Yang, S. Q. (2005) Cytokines and the pathogenesis of non-alcoholic steatohepatitis. Gut 54, 303-306
41. Beraza, N., Malato, Y., Vander Borght, S., Liedtke, C., Wasmuth, H. E., Dreano, M., de Vos, R., Roskams, T. and Trautwein, C. (2007) Pharmacological IKK2 inhibition blocks liver steatosis and initiation of non-alcoholic steatohepatitis. Gut 57, 655-663 (Pubitemid 351579980)
42. Vinciguerra, M., Veyrat-Durebex, C., Moukil, M. A., Rubbia-Brandt, L., Rohner-Jeanrenaud, F. and Foti, M. (2008) PTEN down-regulation by unsaturated fatty acids triggers hepatic steatosis via an NF-κBp65/mTOR-dependent mechanism. Gastroenterology 134, 268-280
43. Cai, D., Yuan, M., Frantz, F. D., Melendez, P. A., Hansen, L., Lee, J. and Shoelson, S. E. (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB. Nat. Med. 11, 183-190
44. Wunderlich, F. T., Luedde, T., Singer, S., Schmidt- Supprian, M., Baumgartl, J., Schirmacher, P., Pasparakis, M. and Bruning, J. C. (2008) Hepatic NF-κB essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis. Proc. Natl. Acad. Sci. U.S.A. 105, 1297-1302
45. Videla, L. A., Tapia, G., Rodrigo, R., Pettinelli, P., Haim, D., Santibanez, C., Araya, A. V., Smok, G., Csendes, A., Gutierrez, L. et al. (2009) Liver NF-κB andAP-1DNA binding in obese patients. Obesity 17, 973-979
46. Senn, J. J., Klover, P. J., Nowak, I. A., Zimmers, T. A., Koniaris, L. G., Furlanetto, R. W. and Mooney, R. A. (2003) Suppressor of cytokine signalling-3 (SOCS-3) a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J. Biol. Chem. 278, 13740-13746
47. Starr, R., Willson, T. A., Viney, E. M., Murray, L. J. L., Rayner, J. R., Jenkins, B. J., Gonda, T. J., Alexander, W. S., Metcalf, D., Nicola, N. A. and Hilton, D. J. (1997) A family of cytokine-inducible inhibitors of signalling. Nature 387, 917-921
48. Ueki, K., Kondo, T., Tseng, Y. and Kahn, R. (2004) Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance and the metabolic syndrome in the mouse. Proc. Natl. Acad. Sci. U.S.A. 101, 10422-10427
49. Semenkovich, C. F. (1997) Regulation of fatty acid synthase (FAS). Prog. Lipid Res. 36, 43-53 (Pubitemid 27387114)
50. Shimomura, I., Hammer, R. E., Ikemoto, S., Brown, M. S. and Goldstein, J. L. (1999) Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401, 73-76
51. Arkan, M. C., Hevener, A. L., Greten, F. R., Maeda, S., Li, Z., Long, J. M., Wynshaw-Boris, A., Poli, G., Olefsky, J. and Karin, M. (2005) IKK-B links inflammation to obesity-induced insulin resistance. Nat. Med. 11, 191-198
52. Chinetti, G., Fruchart, J. C. and Staels, B. (2000) Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm. Res. 49, 497-505
53. Delerive, P., De Bosscher, K., Besnard, S., Vanden Berghe, W., Peters, J. M., Gonzalez, F. J., Fruchart, J. C., Tedgui, A., Haegeman, G. and Staels, B. (1999) Peroxisome proliferator-activated receptor α negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-κB andAP-1. J. Biol. Chem. 274, 32048-32054
54. Delerive, P., Gervois, P., Fruchart, J. C. and Staels, B. (2000) Induction of IκBα expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-α activators. J. Biol. Chem. 275, 36703-36707
55. Yeon, J. E., Choi, K. M., Baik, S. H., Kim, K. O., Lim, H. J., Park, K. H., Kim, J. Y., Park, J. J., Kim, J. S., Bak, Y. T. et al. (2004) Reduced expression of peroxisome proliferator-activated receptor-α may have an important role in the development of non-alcoholic fatty liver disease. J. Gastroenterol. Hepatol. 19, 799-804
56. Costet, P., Legendre, C., More, J., Edgar, A., Galtier, P. and Pineau, T. (1998) Peroxisome proliferator-activated receptor α-isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis. J. Biol. Chem. 273, 29577-29585
57. Nagasawa, T., Inada, Y., Nakano, S., Tamura, T., Takahashi, T., Maruyama, K., Yamazaki, Y., Kuroda, J. and Shibata, N. (2006) Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARδ agonist, on development of steatohepatitis in mice fed a methionine-and choline-deficient diet. Eur. J. Pharmacol. 536, 182-191
58. Walsh, K. and Alexander, G. J. (2001) Update on chronic viral hepatitis. Postgrad. Med. J. 77, 498-505
59. Lucito, R. and Schneider, R. J. (1992) Hepatitis B virus X protein activates transcription factor NF-κB without a requirement for protein kinase C. J. Virol. 66, 983-991
60. Chirillo, P., Falco, M., Puri, P. L., Artini, M., Balsano, C., Levrero, M. and Natoli, G. (1996) Hepatitis B virus pX activates NF-κB-dependent transcription through a Raf-independent pathway. J. Virol. 70, 641-646
61. Feitelson, M. A. and Duan, L. X. (1997) Hepatitis B virus X antigen in the pathogenesis of chronic infections and the development of hepatocellular carcinoma. Am. J. Pathol. 150, 1141-1157
62. Tai, D. I., Tsai, S. L., Chen, Y. M., Chuang, Y. L., Peng, C. Y., Sheen, I. S., Yeh, C. T., Chang, K. S., Huang, S. N., Kuo, G. C. and Liaw, Y. F. (2000) Activation of nuclear factor κB in hepatitis C virus infection: implications for pathogenesis and hepatocarcinogenesis. Hepatology 31, 656-664
63. You, L. R., Chen, C. M. and Lee, Y. H. (1999) Hepatitis C virus core protein enhances NF-κB signal pathway triggering by lymphotoxin-β receptor ligand and tumor necrosis factor α. J. Virol. 73, 1672-1681
64. Zhu, N., Khoshnan, A., Schneider, R., Matsumoto, M., Dennert, G., Ware, C. and Lai, M. M. (1998) Hepatitis C virus core protein binds to the cytoplasmic domain of tumor necrosis factor (TNF) receptor 1 and enhances TNF-induced apoptosis. J. Virol. 72, 3691-3697 (Pubitemid 28188666)
65. Joo, M., Hahn, Y. S., Kwon, M., Sadikot, R. T., Blackwell, T. S. and Christman, J. W. (2005) Hepatitis C virus core protein suppresses NF-κB activation and cyclooxygenase-2 expression by direct interaction with IκB kinase β. J. Virol. 79, 7648-7657
66. Hassan, M., Selimovic, D., Ghozlan, H. and Abdel-Kader, O. (2007) Induction of high-molecular-weight (HMW) tumor necrosis factor(TNF) α by hepatitis C virus (HCV) non-structural protein 3 (NS3) in liver cells is AP-1 and NF-κB-dependent activation. Cell. Signalling 19, 301-311
67. Fischer, R., Baumert, T. and Blum, H. E. (2007) Hepatitis C virus infection and apoptosis. World J. Gastroenterol. 13, 4865-4872
68. Feitelson, M. A., Reis, H.M. G. P. V., Tufan, N. L. S., Sun, B., Pan, J. and Lian, Z. (2009) Putative roles of hepatitis B x antigen in the pathogenesis of chronic liver disease. Cancer Lett. 286, 69-79
69. Pan, J., Duan, L. X., Sun, B. S. and Feitelson, M. A. (2001) Hepatitis B virus X protein protects against anti-Fas-mediated apoptosis in human liver cells by inducing NF-κB. J. Gen. Virol. 82, 171-182
70. Pan, J., Lian, Z., Wallett, S. and Feitelson, M. A. (2007) The hepatitis B x antigen effector, URG7, blocks tumour necrosis factor α mediated apoptosis by activation of phosphoinositol 3-kinase and B-catenin. J. Gen. Virol. 88, 3275-3285
71. Lian, Z., Liu, J., Pan, J., Tufan, N. L. S., Zhu, M., Arbuthnott, P., Kew, M., Clayton, M. M. and Feitelson, M. A. (2001) A cellular gene up-regulated by hepatitis B virus-encoded X antigen promotes hepatocellular growth and survival. Hepatology 34, 146-157 (Pubitemid 32591495)
72. Ohata, K., Ichikawa, T., Nakao, K., Shigeno, M., Nishimura, D., Ishikawa, H., Hamasaki, K. and Eguchi, K. (2003) Interferon α inhibits the nuclear factor κB activation triggered by X gene product of hepatitis B virus in human hepatoma cells. FEBS Lett. 553, 304-308
73. Fausto, N., Campbell, J. S. and Riehle, K. J. (2006) Liver regeneration. Hepatology 43, S45-S53
74. Cressman, D. E., Greenbaum, L. E., Haber, B. A. and Taub, R. (1994) Rapid activation of post-hepatectomy factor/nuclear factor κB in hepatocytes, a primary response in the regenerating liver. J. Biol. Chem. 269, 30429-30435
75. Kirillova, I., Chaisson, M. and Fausto, N. (1999) Tumor necrosis factor induces DNA replication in hepatic cells through nuclear factor κB activation. Cell Growth Differ. 10, 819-828 (Pubitemid 30036254)
76. Iimuro, Y., Nishiura, T., Hellerbrand, C., Behrns, K. E., Schoonhoven, R., Grisham, J.W. and Brenner, D. A. (1998) NFκB prevents apoptosis and liver dysfunction during liver regeneration. J. Clin. Invest. 101, 802-811
77. Plumpe, J., Malek, N. P., Bock, C. T., Rakemann, T., Manns, M. P. and Trautwein, C. (2000) NF-κB determines between apoptosis and proliferation in hepatocytes during liver regeneration. Am. J. Physiol. Gastrointest. Liver Physiol. 278, G173-G183
78. Chaisson, M. L., Brooling, J. T., Ladiges, W., Tsai, S. and Fausto, N. (2002) Hepatocyte-specific inhibition of NF-κB leads to apoptosis after TNF treatment, but not after partial hepatectomy. J. Clin. Invest. 110, 193-202
79. Laurent, S., Horsmans, Y., Starkel, P., Leclercq, I., Sempoux, C. and Lambotte, L. (2005) Disrupted NF-κB activation after partial hepatectomy does not impair hepatocyte proliferation in rats. World J. Gastroenterol. 11, 7345-7350
80. Malato, Y., Sander, L. E., Liedtke, C., Al-Masaoudi, M., Tacke, F., Trautwein, C. and Beraza, N. (2008) Hepatocyte-specific inhibitor-of-κB- kinase deletion triggers the innate immune response and promotes earlier cell proliferation during liver regeneration. Hepatology 47, 2036-2050
81. Yang, L., Magness, S. T., Bataller, R., Rippe, R. A. and Brenner, D. A. (2005) NF-κB activation in Kupffer cells after partial hepatectomy. Am. J. Physiol. Gastrointest. Liver Physiol. 289, G530-G538
82. Rai, R. M., Yang, S. Q., McClain, C., Karp, C. L., Klein, A. S. and Diehl, A. M. (1996) Kupffer cell depletion by gadolinium chloride enhances liver regeneration after partial hepatectomy in rats. Am. J. Physiol. 270, G909-G918
83. Abshagen, K., Eipel, C., Kalff, J. C., Menger, M. D. and Vollmar, B. (2007) Loss of NF-κB activation in Kupffer cell-depleted mice impairs liver regeneration after partial hepatectomy. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G1570-G1577
84. Selzner, N., Rudiger, H., Graf, R. and Clavien, P. A. (2003) Protective strategies against ischemic injury of the liver. Gastroenterology 125, 917-936 (Pubitemid 37070708)
85. Bradham, C. A., Stachlewitz, R. F., Gao, W., Qian, T., Jayadev, S., Jenkins, G., Hannun, Y., Lemasters, J. J., Thurman, R. G. and Brenner, D. A. (1997) Reperfusion after liver transplantation in rats differentially activates the mitogen-activated protein kinases. Hepatology 25, 1128-1135 (Pubitemid 27199939)
86. Zwacka, R. M., Zhang, Y., Zhou, W., Halldorson, J. and Engelhardt, J. F. (1998) Ischemia/reperfusion injury in the liver of BALB/c mice activates AP-1 and nuclear factor κB independently of IκB degradation. Hepatology 28, 1022-1030
87. Fan, C., Li, Q., Ross, D. and Engelhardt, J. F. (2003) Tyrosine phosphorylation of IκBα activates NFκB through a redox-regulated and c-Src-dependent mechanism following hypoxia/reoxygenation. J. Biol. Chem. 278, 2072-2080
88. Beraza, N., Ludde, T., Assmus, U., Roskams, T., Vander Borght, S. and Trautwein, C. (2007) Hepatocyte-specific IKK γ/NEMO expression determines the degree of liver injury. Gastroenterology 132, 2504-2517
89. Luedde, T., Assmus, U., Wustefeld, T., Meyer zu Vilsendorf, A., Roskams, T., Schmidt-Supprian, M., Rajewsky, K., Brenner, D. A., Manns, M. P., Pasparakis, M. and Trautwein, C. (2005) Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury. J. Clin. Invest. 115, 849-859
90. Suetsugu, H., Iimuro, Y., Uehara, T., Nishio, T., Harada, N., Yoshida, M., Hatano, E., Son, G., Fujimoto, J. and Yamaoka, Y. (2005) Nuclear factor κB inactivation in the rat liver ameliorates short term total warm ischaemia/reperfusion injury. Gut 54, 835-842
91. Teoh, N., Dela Pena, A. and Farrell, G. (2002) Hepatic ischemic preconditioning in mice is associated with activation of NF-κB, p38 kinase, and cell cycle entry. Hepatology 36, 94-102
92. Kuboki, S., Okaya, T., Schuster, R., Blanchard, J., Denenberg, A., Wong, H. R. and Lentsch, A. B. (2007) Hepatocyte NF-κB activation is hepatoprotective during ischemia-reperfusion injury and is augmented by ischemic hypothermia. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G201-G207
93. Kuboki, S., Sakai, N., Clarke, C., Schuster, R., Blanchard, J., Edwards, M. J. and Lentsch, A. B. (2009) The peptidyl-prolyl isomerase, Pin1, facilitates NF-κB binding in hepatocytes and protects against hepatic ischemia/reperfusion injury. J. Hepatol. 51, 296-306
94. Schwabe, R. F., Schnabl, B., Kweon, Y. O. and Brenner, D. A. (2001) CD40 activates NF-κB and c-Jun N-terminal kinase and enhances chemokine secretion on activated human hepatic stellate cells. J. Immunol. 166, 6812-6819
95. Wright, M. C., Issa, R., Smart, D. E., Trim, N., Murray, G. I., Primrose, J. N., Arthur, M. J., Iredale, J. P. and Mann, D. A. (2001) Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats. Gastroenterology 121, 685-698 (Pubitemid 32822584)
96. Douglass, A., Wallace, K., Parr, R., Park, J., Durward, E., Broadbent, I., Barelle, C., Porter, A. J. and Wright, M. C. (2008) Antibody-targeted myofibroblast apoptosis reduces fibrosis during sustained liver injury. J. Hepatol. 49, 88-98
97. Oakley, F., Meso, M., Iredale, J. P., Green, K., Marek, C. J., Zhou, X., May, M. J., Millward-Sadler, H., Wright, M. C. and Mann, D. A. (2005) Inhibition of inhibitor of κB kinases stimulates hepatic stellate cell apoptosis and accelerated recovery from rat liver fibrosis. Gastroenterology 128, 108-120
98. Watson, M. R., Wallace, K., Gieling, R. G., Manas, D. M., Jaffray, E., Hay, R. T., Mann, D. A. and Oakley, F. (2008) NF-κB is a critical regulator of the survival of rodent and human hepatic myofibroblasts. J. Hepatol. 48, 589-597
99. Mann, D. A. and Smart, D. E. (2002) Transcriptional regulation of hepatic stellate cell activation. Gut 50, 891-896 (Pubitemid 34539057)
100. Oakley, F., Teoh, V., Ching, A. S. G., Bataller, R., Colmenero, J., Jonsson, J. R., Eliopoulos, A. G., Watson, M. R., Manas, D. and Mann, D. A. (2009) Angiotensin II activates IκB kinase phosphorylation of RelA at Ser 536 to promote myofibroblast survival and liver fibrosis. Gastroenterology 136, 2334-2344
101. Ruddell, R. G., Knight, B., Tirnitz-Parker, J. E., Akhurst, B., Summerville, L., Subramaniam, V. N., Olynyk, J. K. and Ramm, G. A. (2009) Lymphotoxin-β receptor signaling regulates hepatic stellate cell function and wound healing in a murine model of chronic liver injury. Hepatology 49, 227-239
102. Prieto, J. (2008) Inflammation, HCC and sex: IL-6 in the centre of the triangle. J. Hepatol. 48, 380-381
103. Nakagawa, H., Maeda, S., Yoshida, H., Tateishi, R., Masuzaki, R., Ohki, T., Hayakawa, Y., Kinoshita, H., Yamakado, M., Kato, N. et al. (2009) Serum IL-6 levels and the risk for hepatocarcinogenesis in chronic hepatitis C patients: An analysis based on gender differences. Int. J. Cancer 125, 2264-2269
104. Pikarsky, E., Porat, R. M., Stein, I., Abramovitch, R., Amit, S., Kasem, S., Gutkovich-Pyest, E., Urieli-Shoval, S., Galun, E. and Ben-Neriah, Y. (2004) NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461-466 (Pubitemid 39329586)
105. Maeda, S., Kamata, H., Luo, J. L., Leffert, H. and Karin, M. (2005) IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121, 977-990
106. Sakurai, T., Maeda, S., Chang, L. and Karin, M. (2006) Loss of hepatic NF-κB activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc. Natl. Acad. Sci. U.S.A. 103, 10544-10551
107. Koch, K. S., Maeda, S., He, G., Karin, M. and Leffert, H. L. (2009) Targeted deletion of hepatocyte IKKβ confers growth advantages. Biochem. Biophys. Res. Commun. 380, 349-354
108. Luedde, T., Beraza, N., Kotsikoris, V., van Loo, G., Nenci, A., De Vos, R., Roskams, T., Trautwein, C. and Pasparakis, M. (2007) Deletion of NEMO/IKKγ in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 11, 119-132
109. Beraza, N., Malato, Y., Sander, L. E., Al-Masaoudi, M., Freimuth, J., Riethmacher, D., Gores, G. J., Roskams, T., Liedtke, C. and Trautwein, C. (2009) Hepatocyte-specific NEMO deletion promotes NK/NKT cell- and TRAIL-dependent liver damage. J. Exp. Med. 206, 1727-1737
110. Geisler, F., Algul, H., Paxian, S. and Schmid, R. M. (2007) Genetic inactivation of RelA/p65 sensitizes adult mouse hepatocytes to TNF-induced apoptosis in vivo and in vitro. Gastroenterology 132, 2489-2503
111. O'Neil, B. H., Buzkova, P., Farrah, H., Kashatus, D., Sanoff, H., Goldberg, R. M., Baldwin, A. S. and Funkhouser, W. K. (2007) Expression of nuclear factor-κB family proteins in hepatocellular carcinomas. Oncology 72, 97-104
112. Oakley, F., Mann, J., Nailard, S., Smart, D. E., Mungalsingh, N., Constandinou, C., Ali, S., Wilson, S. J., Millward-Sadler, H., Iredale, J. P. and Mann, D. A. (2005) Nuclear factor-κB1 (p50) limits the inflammatory and fibrogenic responses to chronic injury. Am. J. Pathol. 166, 695-708
113. Gieling, R. G., Elsharkawy, A. M., Caamano, J. H., Cowie, D. E., Wright, M. C., Ebrahimkhani, M. R., Burt, A. D., Mann, J., Raychaudhuri, P., Liou, H.-C. et al. (2009) The c-Rel subunit of nuclear factor-κB regulates liver inflammation, wound-healing and hepatocyte proliferation, Hepatology, doi: 10.1002/hep.23385
114. Perkins, N. D. (2007) Integrating cell-signalling pathways with NF-κB and IKK function. Nat. Rev. Mol. Cell. Biol. 8, 49-62