• 1
    Montagnani C, Kappler C, Reichhart J M, Escoubas J M. Cg-Rel, the first Rel/NF-kappaB homolog characterized in a mollusk, the Pacific oyster Crassostrea gigas. FEBS Lett 2004; 561: 7582.
  • 2
    Ferrandon D, Imler J L, Hoffmann J A. Sensing infection in Drosophila: toll and beyond. Semin Immunol 2004; 16: 4353.
  • 3
    Kinoshita T, Miyajima A. Cytokine regulation of liver development. Biochim Biophys Acta 2002; 1592: 30312.
  • 4
    Neuman M G. Apoptosis in diseases of the liver. Crit Rev Clin Lab Sci 2001; 38: 10966.
  • 5
    Luedde T, Liedtke C, Manns M P, Trautwein C. Losing balance: cytokine signalling and cell death in the context of hepatocyte injury and hepatic failure. Eur Cytokine Network 2002; 13: 37783.
  • 6
    Ghosh S, May M J, Kopp E B. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 1998; 16: 22560.
  • 7
    Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell 2002; 109 (Suppl.): S8196.
  • 8
    Schmitz M L, Baeuerle P A. The p65 subunit is responsible for the strong transcription activating potential of NF-kappa B. EMBO J 1991; 10: 380517.
  • 9
    Baeuerle P A, Baltimore D. NF-kappa B: ten years after. Cell 1996; 87: 1320.
  • 10
    Arenzana-Seisdedos F, Turpin P, Rodriguez M, et al. Nuclear localization of I kappa B alpha promotes active transport of NF-kappa B from the nucleus to the cytoplasm. J Cell Sci 1997; 110: 36978.
  • 11
    Karin M. How NF-kappaB is activated: the role of the IkappaB kinase (IKK) complex. Oncogene 1999; 18: 686774.
  • 12
    Senftleben U, Cao Y, Xiao G, et al. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signalling pathway. Science 2001; 293: 14959.
  • 13
    Xiao G, Harhaj E W, Sun S C. NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100. Mol Cell 2001; 7: 4019.
  • 14
    Muller J R, Siebenlist U. Lymphotoxin beta receptor induces sequential activation of distinct NF-kappa B factors via separate signalling pathways. J Biol Chem 2003; 278: 1200612.
  • 15
    Pomerantz J L, Baltimore D. Two pathways to NF-kappaB. Mol Cell 2002; 10: 6935.
  • 16
    Tergaonkar V, Bottero V, Ikawa M, Li Q, Verma I M. IkappaB kinase-independent IkappaBalpha degradation pathway: functional NF-kappaB activity and implications for cancer therapy. Mol Cell Biol 2003; 23: 807083.
  • 17
    Kato T Jr., Delhase M, Hoffmann A, Karin M. CK2 is a C-Terminal IkappaB Kinase responsible for NF-kappaB activation during the UV response. Mol Cell 2003; 12: 82939.
  • 18
    Panta G R, Kaur S, Cavin L G, et al. ATM and the catalytic subunit of DNA-dependent protein kinase activate NF-kappaB through a common MEK/extracellular signal-regulated kinase/p90 (rsk) signalling pathway in response to distinct forms of DNA damage. Mol Cell Biol 2004; 24: 182335.
  • 19
    Schouten G J, Vertegaal A C, Whiteside S T, et al. IkappaB alpha is a target for the mitogen-activated 90 kDa ribosomal S6 kinase. EMBO J 1997; 16: 313344.
  • 20
    Chen L F, Greene W C. Shaping the nuclear action of NF-kappaB. Nat Rev Mol Cell Biol 2004; 5: 392401.
  • 21
    Schmitz M L, Mattioli I, Buss H, Kracht M. NF-κB: a multi-faceted transcription factor regulated at several levels. Chembiochem 2004; 5: 134858.
  • 22
    Carswell E A, Old L J, Kassel R L, et al. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 1975; 72: 366670.
  • 23
    Kimura K, Taguchi T, Urushizaki I, et al. Phase I study of recombinant human tumor necrosis factor. Cancer Chemother Pharmacol 1987; 20: 2239.
  • 24
    Feinberg B, Kurzrock R, Talpaz M, et al. A phase I trial of intravenously-administered recombinant tumor necrosis factor-alpha in cancer patients. J Clin Oncol 1988; 6: 132834.
  • 25
    Colletti L M, Remick D G, Burtch G D, et al. Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat. J Clin Invest 1990; 85: 193643.
  • 26
    Felver M E, Mezey E, Mcguire M, et al. Plasma tumor necrosis factor alpha predicts decreased long-term survival in severe alcoholic hepatitis. Alcohol Clin Exp Res 1990; 14: 2559.
  • 27
    Gonzalez-Amaro R, Garcia-Monzon C, Garcia-Buey L, et al. Induction of tumor necrosis factor alpha production by human hepatocytes in chronic viral hepatitis. J Exp Med 1994; 179: 8418.
  • 28
    Leist M, Gantner F, Naumann H, et al. Tumor necrosis factor-induced apoptosis during the poisoning of mice with hepatotoxins. Gastroenterology 1997; 112: 92334.
  • 29
    Muto Y, Nouri-Aria K T, Meager A, et al. Enhanced tumour necrosis factor and interleukin-1 in fulminant hepatic failure. Lancet 1988; 2: 724.
  • 30
    Bird G L, Sheron N, Goka A K, et al. Increased plasma tumor necrosis factor in severe alcoholic hepatitis. Ann Intern Med 1990; 112: 91720.
  • 31
    Streetz K, Leifeld L, Grundmann D, et al. Tumor necrosis factor alpha in the pathogenesis of human and murine fulminant hepatic failure. Gastroenterology 2000; 119: 44660.
  • 32
    Pfeffer K, Matsuyama T, Kundig T M, et al. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 1993; 73: 45767.
  • 33
    Gantner F, Leist M, Lohse A W, et al. Concanavalin A-induced T-cell-mediated hepatic injury in mice: the role of tumor necrosis factor. Hepatology 1995; 21: 1908.
  • 34
    Chen G, Goeddel D V. TNF-R1 signalling: a beautiful pathway. Science 2002; 296: 16345.
  • 35
    Yamamoto Y, Gaynor R B. IkappaB kinases: key regulators of the NF-kappaB pathway. Trends Biochem Sci 2004; 29: 729.
  • 36
    Didonato J A, Hayakawa M, Rothwarf D M, et al. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature 1997; 388: 54854.
  • 37
    Regnier C H, Song H Y, Gao X, et al. Identification and characterization of an IkappaB kinase. Cell 1997; 90: 37383.
  • 38
    Mercurio F, Murray B W, Shevchenko A, et al. IkappaB kinase (IKK)-associated protein 1, a common component of the heterogeneous IKK complex. Mol Cell Biol 1999; 19: 152638.
  • 39
    Rothwarf D M, Zandi E, Natoli G, Karin M. IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature 1998; 395: 297300.
  • 40
    Yamaoka S, Courtois G, Bessia C, et al. Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation. Cell 1998; 93: 123140.
  • 41
    Zandi E, Chen Y, Karin M. Direct phosphorylation of IkappaB by IKKalpha and IKKbeta: discrimination between free and NF-kappaB-bound substrate. Science 1998; 281: 13603.
  • 42
    Delhase M, Hayakawa M, Chen Y, Karin M. Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation. Science 1999; 284: 30913.
  • 43
    Mercurio F, Zhu H, Murray B W, et al. IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science 1997; 278: 8606.
  • 44
    Woronicz J D, Gao X, Cao Z, et al. IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science 1997; 278: 8669.
  • 45
    Zandi E, Rothwarf D M, Delhase M, et al. The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell 1997; 91: 24352.
  • 46
    Devin A, Cook A, Lin Y, et al. The distinct roles of TRAF2 and RIP in IKK activation by TNF-R1: TRAF2 recruits IKK to TNF-R1 while RIP mediates IKK activation. Immunity 2000; 12: 41929.
  • 47
    Devin A, Lin Y, Yamaoka S, et al. The alpha and beta subunits of IkappaB kinase (IKK) mediate TRAF2-dependent IKK recruitment to tumor necrosis factor (TNF) receptor 1 in response to TNF. Mol Cell Biol 2001; 21: 398694.
  • 48
    Zhang S Q, Kovalenko A, Cantarella G, Wallach D. Recruitment of the IKK signalosome to the p55 TNF receptor: RIP and A20 bind to NEMO (IKK gamma) upon receptor stimulation. Immunity 2000; 12: 30111.
  • 49
    Liu Z G, Hsu H, Goeddel D V, Karin M. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Cell 1996; 87: 56576.
  • 50
    Fitzgerald M J, Webber E M, Donovan J R, Fausto N. Rapid DNA binding by nuclear factor kappa B in hepatocytes at the start of liver regeneration. Cell Growth Differ 1995; 6: 41727.
  • 51
    Lehmann V, Freudenberg M A, Galanos C. Lethal toxicity of lipopolysaccharide and tumor necrosis factor in normal and D-galactosamine-treated mice. J Exp Med 1987; 165: 65763.
  • 52
    Leist M, Gantner F, Bohlinger I, et al. Murine hepatocyte apoptosis induced in vitro and in vivo by TNF-alpha requires transcriptional arrest. J Immunol 1994; 153: 177888.
  • 53
    Nagaki M, Naiki T, Brenner D A, et al. Tumor necrosis factor alpha prevents tumor necrosis factor receptor-mediated mouse hepatocyte apoptosis, but not fas-mediated apoptosis: role of nuclear factor-kappaB. Hepatology 2000; 32: 12729.
  • 54
    Bellas R E, Fitzgerald M J, Fausto N, Sonenshein G E. Inhibition of NF-kappa B activity induces apoptosis in murine hepatocytes. Am J Pathol 1997; 151: 8916.
  • 55
    Beg A A, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 1996; 274: 7824.
  • 56
    Doi T S, Marino M W, Takahashi T, et al. Absence of tumor necrosis factor rescues RelA-deficient mice from embryonic lethality. Proc Natl Acad Sci USA 1999; 96: 29949.
  • 57
    Grossmann M, Metcalf D, Merryfull J, et al. The combined absence of the transcription factors Rel and RelA leads to multiple hemopoietic cell defects. Proc Natl Acad Sci USA 1999; 96: 1184853.
  • 58
    Hu Y, Baud V, Delhase M, et al. Abnormal morphogenesis but intact IKK activation in mice lacking the IKKalpha subunit of IkappaB kinase. Science 1999; 284: 31620.
  • 59
    Takeda K, Takeuchi O, Tsujimura T, et al. Limb and skin abnormalities in mice lacking IKKalpha. Science 1999; 284: 3136.
  • 60
    Li Q, Van Antwerp D, Mercurio F, et al. Severe liver degeneration in mice lacking the IkappaB kinase 2 gene. Science 1999; 284: 3215.
  • 61
    Li Z W, Chu W, Hu Y, et al. The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis. J Exp Med 1999; 189: 183945.
  • 62
    Tanaka M, Fuentes M E, Yamaguchi K, et al. Embryonic lethality, liver degeneration, and impaired NF-kappa B activation in IKK-beta-deficient mice. Immunity 1999; 10: 4219.
  • 63
    Rudolph D, Yeh W C, Wakeham A, et al. Severe liver degeneration and lack of NF-kappaB activation in NEMO/IKKgamma-deficient mice. Genes Dev 2000; 14: 85462.
  • 64
    Schwabe R F, Bennett B L, Manning A M, Brenner D A. Differential role of I kappa B kinase 1 and 2 in primary rat hepatocytes. Hepatology 2001; 33: 8190.
  • 65
    Luedde T, Assmus U, Wustefeld T, et al. Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury. J Clin Invest 2005; 115: 84959.
  • 66
    Gantner F, Leist M, Lohse A W, et al. Concanavalin A-induced T-cell-mediated hepatic injury in mice: the role of tumor necrosis factor. Hepatology 1995; 21: 1908.
  • 67
    Maeda S, Chang L, Li Z W, et al. IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFalpha. Immunity 2003; 19: 72537.
  • 68
    Trautwein C, Rakemann T, Brenner D A, et al. Concanavalin A-induced liver cell damage: activation of intracellular pathways triggered by tumor necrosis factor in mice. Gastroenterology 1998; 114: 103545.
  • 69
    Lavon I, Goldberg I, Amit S, et al. High susceptibility to bacterial infection, but no liver dysfunction, in mice compromised for hepatocyte NF-kappaB activation. Nat Med 2000; 6: 5737.
  • 70
    Ryo K, Kamogawa Y, Ikeda I, et al. Significance of Fas antigen-mediated apoptosis in human fulminant hepatic failure. Am J Gastroenterol 2000; 95: 204755.
    Direct Link:
  • 71
    Nagata S, Golstein P. The Fas death factor. Science 1995; 267: 144956.
  • 72
    Marusawa H, Hijikata M, Watashi K, Chiba T, Shimotohno K. Regulation of Fas-mediated apoptosis by NF-kappaB activity in human hepatocyte derived cell lines. Microbiol Immunol 2001; 45: 4839.
  • 73
    Kuhnel F, Zender L, Paul Y, et al. NFkappaB mediates apoptosis through transcriptional activation of Fas (CD95) in adenoviral hepatitis. J Biol Chem 2000; 275: 64217.
  • 74
    Deveraux Q L, Roy N, Stennicke H R, et al. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J 1998; 17: 221523.
  • 75
    Deveraux Q L, Leo E, Stennicke H R, et al. Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases. EMBO J 1999; 18: 524251.
  • 76
    Karin M, Lin A. NF-kappaB at the crossroads of life and death. Nat Immunol 2002; 3: 221227.
  • 77
    Barkett M, Gilmore T D. Control of apoptosis by Rel/NF-kappaB transcription factors. Oncogene 1999; 18: 691024.
  • 78
    Lin A. Activation of the JNK signalling pathway: breaking the brake on apoptosis. Bioessays 2003; 25: 1724.
  • 79
    De Smaele E, Zazzeroni F, Papa S, et al. Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling. Nature 2001; 414: 30813.
  • 80
    Lamb J A, Ventura J J, Hess P, et al. JunD mediates survival signalling by the JNK signal transduction pathway. Mol Cell 2003; 11: 147989.
  • 81
    Liedtke C, Plumpe J, Kubicka S, et al. Jun kinase modulates tumor necrosis factor-dependent apoptosis in liver cells. Hepatology 2002; 36: 31525.
  • 82
    Tang G, Minemoto Y, Dibling B, et al. Inhibition of JNK activation through NF-kappaB target genes. Nature 2001; 414: 3137.
  • 83
    Schwabe R F, Uchinami H, Qian T, et al. Differential requirement for c-Jun NH2-terminal kinase in TNFalpha- and Fas-mediated apoptosis in hepatocytes. FASEB J 2004; 18: 7202.
  • 84
    Jaeschke H. Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol 2003; 284: G1526.
  • 85
    Jaeschke H, Smith C V, Mitchell J R. Reactive oxygen species during ischemia-reflow injury in isolated perfused rat liver. J Clin Invest 1988; 81: 12406.
  • 86
    Jaeschke H, Farhood A. Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver. Am J Physiol 1991; 260: G35562.
  • 87
    Jaeschke H. Reactive oxygen and ischemia/reperfusion injury of the liver. Chem Biol Interact 1991; 79: 11536.
  • 88
    Rudiger H A, Clavien P A. Tumor necrosis factor alpha, but not Fas, mediates hepatocellular apoptosis in the murine ischemic liver. Gastroenterology 2002; 122: 20210.
  • 89
    Zwacka R M, Zhang Y, Zhou W, et al. Ischemia/reperfusion injury in the liver of BALB/c mice activates AP-1 and nuclear factor kappaB independently of IkappaB degradation. Hepatology 1998; 28: 102230.
  • 90
    Fan C, Li Q, Ross D, Engelhardt J F. Tyrosine phosphorylation of I kappa B alpha activates NF kappa B through a redox-regulated and c-Src-dependent mechanism following hypoxia/reoxygenation. J Biol Chem 2003; 278: 207280.
  • 91
    Fan C, Li Q, Zhang Y, et al. IkappaBalpha and IkappaBbeta possess injury context-specific functions that uniquely influence hepatic NF-kappaB induction and inflammation. J Clin Invest 2004; 113: 74655.
  • 92
    Fan C, Yang J, Engelhardt J F. Temporal pattern of NFkappaB activation influences apoptotic cell fate in a stimuli-dependent fashion. J Cell Sci 2002; 115: 484353.
  • 93
    Fausto N. Liver regeneration. J Hepatol 2000; 32: 1931.
  • 94
    Michalopoulos G K, Defrances M. Liver regeneration. Adv Biochem Eng Biotechnol 2005; 93: 10134.
  • 95
    Cressman D E, Greenbaum L E, Haber B A, Taub R. Rapid activation of post-hepatectomy factor/nuclear factor kappa B in hepatocytes, a primary response in the regenerating liver. J Biol Chem 1994; 269: 3042935.
  • 96
    Yamada Y, Kirillova I, Peschon J J, Fausto N. Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I tumor necrosis factor receptor. Proc Natl Acad Sci USA 1997; 94: 14416.
  • 97
    Plumpe J, Malek N P, Bock C T, et al. NF-kappaB determines between apoptosis and proliferation in hepatocytes during liver regeneration. Am J Physiol Gastrointest Liver Physiol 2000; 278: G17383.
  • 98
    Iimuro Y, Nishiura T, Hellerbrand C, et al. NFkappaB prevents apoptosis and liver dysfunction during liver regeneration. J Clin Invest 1998; 101: 80211.
  • 99
    Chaisson M L, Brooling J T, Ladiges W, et al. Hepatocyte-specific inhibition of NF-kappaB leads to apoptosis after TNF treatment, but not after partial hepatectomy. J Clin Invest 2002; 110: 193202.
  • 100
    Lieber A, He C Y, Meuse L, et al. The role of Kupffer cell activation and viral gene expression in early liver toxicity after infusion of recombinant adenovirus vectors. J Virol 1997; 71: 8798807.
  • 101
    Hellerbrand C, Jobin C, Iimuro Y, et al. Inhibition of NFkappaB in activated rat hepatic stellate cells by proteasome inhibitors and an IkappaB super-repressor. Hepatology 1998; 27: 128595.
  • 102
    Pasparakis M. Making gene-modified mice. Ernst Schering Res Found Workshop 2005; 50: 126.
  • 103
    Maeda S, Kamata H, Luo J L, et al. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 2005; 121: 97790.
  • 104
    Hanahan D, Weinberg R A. The hallmarks of cancer. Cell 2000; 100: 5770.
  • 105
    Masui T, Nakanishi H, Inada K, et al. Highly metastatic hepatocellular carcinomas induced in male F344 rats treated with N-nitrosomorpholine in combination with other hepatocarcinogens show a high incidence of p53 gene mutations along with altered mRNA expression of tumor-related genes. Cancer Lett 1997; 112: 3345.
  • 106
    Murakami Y, Hayashi K, Hirohashi S, Sekiya T. Aberrations of the tumor suppressor p53 and retinoblastoma genes in human hepatocellular carcinomas. Cancer Res 1991; 51: 55205.
  • 107
    Mauad T H, Van Nieuwkerk C M, Dingemans K P, et al. Mice with homozygous disruption of the mdr2 P-glycoprotein gene. A novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis. Am J Pathol 1994; 145: 123745.
  • 108
    Pikarsky E, Porat R M, Stein I, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 2004; 43: 4616.
  • 109
    Streetz K L, Luedde T, Manns M P, Trautwein C. Interleukin 6 and liver regeneration. Gut 2000; 47: 30912.
  • 110
    Trautwein C, Boker K, Manns M P. Hepatocyte and immune system: acute phase reaction as a contribution to early defence mechanisms. Gut 1994; 35: 11636.
  • 111
    Zhang D, Sun M, Samols D, Kushner I. STAT3 participates in transcriptional activation of the C-reactive protein gene by interleukin-6. J Biol Chem 1996; 271: 95039.
  • 112
    Catlett-Falcone R, Landowski T H, Oshiro M M, et al. Constitutive activation of Stat3 signalling confers resistance to apoptosis in human U266 myeloma cells. Immunity 1999; 10: 10515.
  • 113
    Chen R H, Chang M C, Su Y H, et al. Interleukin-6 inhibits transforming growth factor-beta-induced apoptosis through the phosphatidylinositol 3-kinase/Akt and signal transducers and activators of transcription 3 pathways. J Biol Chem 1999; 274: 230139.
  • 114
    Ludwig H, Nachbaur D M, Fritz E, et al. Interleukin-6 is a prognostic factor in multiple myeloma. Blood 1991; 77: 27945.
  • 115
    Tsutamoto T, Hisanaga T, Wada A, et al. Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure. J Am Coll Cardiol 1998; 31: 3918.
  • 116
    Streetz K L, Wustefeld T, Klein C, et al. Lack of gp130 expression in hepatocytes promotes liver injury. Gastroenterology 2003; 125: 53243.
  • 117
    Streetz K L, Tacke F, Leifeld L, et al. Interleukin 6/gp130-dependent pathways are protective during chronic liver diseases. Hepatology 2003; 38: 21829.
  • 118
    Klein C, Wustefeld T, Assmus U, et al. The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury. J Clin Invest 2005; 115: 8609.
  • 119
    Karin M, Cao Y, Greten F R, Li Z W. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2002; 2: 30110.