Skip to main content
SpringerLink
Log in

NF-κB

  • Chapter
  • First Online:
Signaling Pathways in Liver Diseases

Abstract

Nuclear factor (NF)-κB was first described in 1986 by the group of Nobel Prize winner David Baltimore as a nuclear factor necessary for immunoglobulin κ light chain transcription [1, 2]. It exists in virtually all known cell types and mitochondria [3, 4] and regulates the transcription of an exceptionally large number of genes, including those involved in immune and inflammatory response, cell death, and proliferation [5]. In the last few years, tremendous progress has been made in advancing our understanding of the complex functions of this pathway in vivo. In particular, studies using conditional knockout technology in mice to specifically inactivate this pathway in certain tissues have highlighted the crucial function of NF-κB in linking innate immune responses and cytokine signaling to all kinds of pathological conditions that had not initially been associated with inflammation [6]. As the liver is a preferred source of and target for cytokines, it is not surprising that the NF-κB pathway influences nearly all physiological processes in the liver and hepatic diseases such as acute liver failure, hepatocarcinogenesis, and hepatic fibrogenesis [7]. On the basis of its fundamental importance, it is more than likely that novel molecular therapies targeting members of the NF-κB pathway will be developed in the near future and will enter daily clinical practice. Therefore, to understand the basic principles of this pathway, we will give a short introduction to the structure and basic activation pathways of NF-κB, describe its role in modulating hepatocyte cell death, and then focus on its role in hepatic disease conditions, namely hepatocarcinogenesis, liver fibrosis, and hepatitis.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Sen R, Baltimore D (1986) Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 46:705–716

    Article  PubMed  CAS  Google Scholar 

  2. Sen R, Baltimore D (1986) Inducibility of κ immunoglobulin enhancer-binding protein NF-κ B by a posttranslational mechanism. Cell 47:921–928

    Article  PubMed  CAS  Google Scholar 

  3. Cogswell PC, Kashatus DF, Keifer JA et al (2003) NF-κB and I κ B alpha are found in the mitochondria. Evidence for regulation of mitochondrial gene expression by NF-κB. J Biol Chem 278:2963–2968

    Article  PubMed  CAS  Google Scholar 

  4. Hayden MS, Ghosh S (2008) Shared principles in NF-κB signaling. Cell 132:344–362

    Article  PubMed  CAS  Google Scholar 

  5. Ghosh S, Hayden MS (2008) New regulators of NF-κB in inflammation. Nat Rev Immunol 8:837–848

    Article  PubMed  CAS  Google Scholar 

  6. Pasparakis M, Luedde T, Schmidt-Supprian M (2006) Dissection of the NF-κB signalling cascade in transgenic and knockout mice. Cell Death Differ 13(5):861–872

    Article  PubMed  CAS  Google Scholar 

  7. Luedde T, Beraza N, Trautwein C (2006) Evaluation of the role of nuclear factor-κB signaling in liver injury using genetic animal models. J Gastroenterol Hepatol 21(Suppl 3):S43–S46

    Article  CAS  Google Scholar 

  8. Montagnani C, Kappler C, Reichhart JM, Escoubas JM (2004) Cg-Rel, the first Rel/NF-κB homolog characterized in a mollusk, the Pacific oyster Crassostrea gigas. FEBS Lett 561:75–82

    Article  PubMed  CAS  Google Scholar 

  9. Ferrandon D, Imler JL, Hoffmann JA (2004) Sensing infection in Drosophila: Toll and beyond. Semin Immunol 16:43–53

    Article  PubMed  CAS  Google Scholar 

  10. Xiao C, Ghosh S (2005) NF-κB, an evolutionarily conserved mediator of immune and inflammatory responses. Adv Exp Med Biol 560:41–45

    Article  PubMed  CAS  Google Scholar 

  11. Schmitz ML, Mattioli I, Buss H, Kracht M (2004) NF-κB: a multifaceted transcription factor regulated at several levels. Chem Biochem 5:1348–1358

    CAS  Google Scholar 

  12. Schmitz ML, Baeuerle PA (1991) The p65 subunit is responsible for the strong transcription activating potential of NF-κ B. EMBO J 10:3805–3817

    PubMed  CAS  Google Scholar 

  13. Amir RE, Haecker H, Karin M, Ciechanover A (2004) Mechanism of processing of the NF-κB2 p100 precursor: identification of the specific polyubiquitin chain-­anchoring lysine residue and analysis of the role of NEDD8-modification on the SCF(beta-TrCP) ubiquitin ligase. Oncogene 23:2540–2547

    Article  PubMed  CAS  Google Scholar 

  14. Karin M (2008) The IκB kinase - a bridge between inflammation and cancer. Cell Res 18:334–342

    Article  PubMed  CAS  Google Scholar 

  15. Saha A, Hammond CE, Trojanowska M, Smolka AJ (2008) Helicobacter pylori-induced H, K-ATPase alpha-subunit gene repression is mediated by NF-κB p50 homodimer promoter binding. Am J Physiol Gastrointest Liver Physiol 294:G795–807

    Article  CAS  Google Scholar 

  16. Hoffmann A, Natoli G, Ghosh G (2006) Transcriptional regulation via the NF-κB signaling module. Oncogene 25:6706–6716

    Article  PubMed  CAS  Google Scholar 

  17. Viatour P, Merville MP, Bours V, Chariot A (2005) Phosphorylation of NF-κB and IκB proteins: implications in cancer and inflammation. Trends Biochem Sci 30:43–52

    Article  PubMed  CAS  Google Scholar 

  18. Basak S, Kim H, Kearns JD et al (2007) A fourth IκB protein within the NF-κB signaling module. Cell 128:369–381

    Article  PubMed  CAS  Google Scholar 

  19. Renzana-Seisdedos F, Turpin P, Rodriguez M et al (1997) Nuclear localization of I κB alpha promotes active transport of NF-κ B from the nucleus to the cytoplasm. J Cell Sci 110(Pt 3):369–378

    Google Scholar 

  20. DiDonato JA, Hayakawa M, Rothwarf DM et al (1997) A cytokine-responsive IκB kinase that activates the transcription factor NF-κB. Nature 388:548–554

    Article  PubMed  CAS  Google Scholar 

  21. Mercurio F, Zhu H, Murray BW et al (1997) IKK-1 and IKK-2: cytokine-activated IκB kinases essential for NF-κB activation. Science 278:860–866

    Article  PubMed  CAS  Google Scholar 

  22. Regnier CH, Song HY, Gao X et al (1997) Identification and characterization of an IκB kinase. Cell 90:373–383

    Article  PubMed  CAS  Google Scholar 

  23. Zandi E, Chen Y, Karin M (1998) Direct phosphorylation of IκB by IKKalpha and IKKbeta: discrimination between free and NF-κB-bound substrate. Science 281: 1360–1363

    Article  PubMed  CAS  Google Scholar 

  24. Delhase M, Hayakawa M, Chen Y, Karin M (1999) Positive and negative regulation of IκB kinase activity through IKKbeta subunit phosphorylation. Science 284:309–313

    Article  PubMed  CAS  Google Scholar 

  25. Woronicz JD, Gao X, Cao Z et al (1997) IκB kinase-beta: NF-κB activation and complex formation with IκB kinase-alpha and NIK. Science 278:866–869

    Article  PubMed  CAS  Google Scholar 

  26. Zandi E, Rothwarf DM, Delhase M et al (1997) The IκB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IκB phosphorylation and NF-κB activation. Cell 91:243–252

    Article  PubMed  CAS  Google Scholar 

  27. Yamaoka S, Courtois G, Bessia C et al (1998) Comple­mentation cloning of NEMO, a component of the IκB kinase complex essential for NF-κB activation. Cell 93: 1231–1240

    Article  PubMed  CAS  Google Scholar 

  28. Rothwarf DM, Zandi E, Natoli G, Karin M (1998) IKK-gamma is an essential regulatory subunit of the IκB kinase complex. Nature 395:297–300

    Article  PubMed  CAS  Google Scholar 

  29. Mercurio F, Murray BW, Shevchenko A et al (1999) IκB kinase (IKK)-associated protein 1, a common component of the heterogeneous IKK complex. Mol Cell Biol 19:1526–1538

    PubMed  CAS  Google Scholar 

  30. Hacker H, Karin M (2006) Regulation and function of IKK and IKK-related kinases. Sci STKE 357: re13

    Google Scholar 

  31. Yaron A, Hatzubai A, Davis M et al (1998) Identification of the receptor component of the IκBalpha-ubiquitin ligase. Nature 396:590–594

    Article  PubMed  CAS  Google Scholar 

  32. Luedde T, Heinrichsdorff J, De Lorenzi R et al (2008) IKK1 and IKK2 cooperate to maintain bile duct integrity in the liver. Proc Natl Acad Sci USA 105:9733–9738

    Article  PubMed  Google Scholar 

  33. Senftleben U, Cao Y, Xiao G et al (2001) Activation by IKKalpha of a second, evolutionary conserved, NF-κB signaling pathway. Science 293:1495–1499

    Article  PubMed  CAS  Google Scholar 

  34. Dejardin E (2006) The alternative NF-κB pathway from biochemistry to biology: pitfalls and promises for future drug development. Biochem Pharmacol 72:1161–1179

    Article  PubMed  CAS  Google Scholar 

  35. Anest V, Hanson JL, Cogswell PC et al (2003) A nucleosomal function for IκB kinase-alpha in NF-κB-dependent gene expression. Nature 423:659–663

    Article  PubMed  CAS  Google Scholar 

  36. Gareus R, Huth M, Breiden B et al (2007) Normal epidermal differentiation but impaired skin-barrier formation upon keratinocyte-restricted IKK1 ablation. Nat Cell Biol 9:461–469

    Article  PubMed  CAS  Google Scholar 

  37. Kato T Jr, Delhase M, Hoffmann A, Karin M (2003) CK2 is a C-terminal IκB kinase responsible for NF-κB activation during the UV response. Mol Cell 12:829–839

    Article  PubMed  CAS  Google Scholar 

  38. Panta GR, Kaur S, Cavin LG et al (2004) ATM and the catalytic subunit of DNA-dependent protein kinase activate NF-κB through a common MEK/extracellular signal-regulated kinase/p90(rsk) signaling pathway in response to distinct forms of DNA damage. Mol Cell Biol 24:1823–1835

    Article  PubMed  CAS  Google Scholar 

  39. Schouten GJ, Vertegaal AC, Whiteside ST et al (1997) IκB alpha is a target for the mitogen-activated 90 kDa ribosomal S6 kinase. EMBO J 16:3133–3144

    Article  PubMed  CAS  Google Scholar 

  40. Tergaonkar V, Bottero V, Ikawa M et al (2003) IκB kinase-independent IκBalpha degradation pathway: functional NF-κB activity and implications for cancer therapy. Mol Cell Biol 23:8070–8083

    Article  PubMed  CAS  Google Scholar 

  41. Wuerzberger-Davis SM, Nakamura Y, Seufzer BJ, Miyamoto S (2007) NF-κB activation by combinations of NEMO SUMOylation and ATM activation stresses in the absence of DNA damage. Oncogene 26:641–651

    Article  PubMed  CAS  Google Scholar 

  42. Salminen A, Suuronen T, Huuskonen J, Kaarniranta K (2008) NEMO shuttle: a link between DNA damage and NF-κB activation in progeroid syndromes? Biochem Biophys Res Commun 367:715–718

    Article  PubMed  CAS  Google Scholar 

  43. Okazaki T, Sakon S, Sasazuki T, Sakurai H et al (2003) Phosphorylation of serine 276 is essential for p65 NF-κB subunit-dependent cellular responses. Biochem Biophys Res Commun 300:807–812

    Article  PubMed  CAS  Google Scholar 

  44. Vermeulen L, De Wilde G, Van Damme P et al (2003) Transcriptional activation of the NF-κB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1). EMBO J 22:1313–1324

    Article  PubMed  CAS  Google Scholar 

  45. Mattioli I, Sebald A, Bucher C et al (2004) Transient and selective NF-κB p65 serine 536 phosphorylation induced by T cell costimulation is mediated by IκB kinase beta and controls the kinetics of p65 nuclear import. J Immunol 172:6336–6344

    PubMed  CAS  Google Scholar 

  46. Schwabe RF, Sakurai H (2005) IKKbeta phosphorylates p65 at S468 in transactivaton domain 2. FASEB J 19:1758–1760

    PubMed  CAS  Google Scholar 

  47. Luedde T, Liedtke C, Manns MP, Trautwein C (2002) Losing balance: cytokine signaling and cell death in the context of hepatocyte injury and hepatic failure. Eur Cytokine Netw 13(4):377–383

    Google Scholar 

  48. Hatano E (2007) Tumor necrosis factor signaling in hepatocyte apoptosis. J Gastroenterol Hepatol 22(Suppl 1):S43–44

    Article  CAS  Google Scholar 

  49. Malhi H, Gores GJ, Lemasters JJ (2006) Apoptosis and necrosis in the liver: a tale of two deaths? Hepatology 43:S31–44

    Article  CAS  Google Scholar 

  50. McDermott MF (2001) TNF and TNFR biology in health and disease. Cell Mol Biol Noisy-le-Grand 47:619–635

    PubMed  CAS  Google Scholar 

  51. FitzGerald MJ, Webber EM, Donovan JR, Fausto N (1995) Rapid DNA binding by nuclear factor κB in ­hepatocytes at the start of liver regeneration. Cell Growth Differ 6: 417–427

    PubMed  CAS  Google Scholar 

  52. Pfeffer K, Matsuyama T, Kundig TM et al (1993) Mice deficient for the 55 kd tumor necrosis factor receptor are ­resistant to endotoxic shock yet succumb to L monocytogenes infection. Cell 73:457–467

    Article  PubMed  CAS  Google Scholar 

  53. Leist M, Gantner F, Bohlinger I et al (1994) Murine hepatocyte apoptosis induced in vitro and in vivo by TNFalpha requires transcriptional arres. J Immunol 153:1778–1788

    PubMed  CAS  Google Scholar 

  54. Lehmann V, Freudenberg MA, Galanos C (1987) Lethal toxicity of lipopolysaccharide and tumor necrosis factor in normal and D-galactosamine-treated mice. J Exp Med 165:657–663

    Article  PubMed  CAS  Google Scholar 

  55. Leist M, Gantner F, Naumann H et al (1997) Tumor necrosis factor-induced apoptosis during the poisoning of mice with hepatotoxins. Gastroenterology 112:923–934

    Article  PubMed  CAS  Google Scholar 

  56. Beg AA, Baltimore D (1996) An essential role for NF-κB in preventing TNF-alpha-induced cell death. Science 274:782–784

    Article  PubMed  CAS  Google Scholar 

  57. Doi TS, Marino MW, Takahashi T et al (1999) Absence of tumor necrosis factor rescues RelA-deficient mice from embryonic lethality. Proc Natl Acad Sci USA 96: 2994–2999

    Article  PubMed  CAS  Google Scholar 

  58. Grossmann M, Metcalf D, Merryfull J et al (1999) The combined absence of the transcription factors Rel and RelA leads to multiple hemopoietic cell defects. Proc Natl Acad Sci USA 96:11848–11853

    Article  PubMed  CAS  Google Scholar 

  59. Li Q, Van Antwerp D, Mercurio F et al (1999) Severe liver degeneration in mice lacking the IκB kinase 2 gene. Science 284:321–325

    Article  PubMed  CAS  Google Scholar 

  60. Li ZW, Chu W, Hu Y et al (1999) The IKKbeta subunit of IκB kinase (IKK) is essential for nuclear factor κB activation and prevention of apoptosis. J Exp Med 189:1839–1845

    Article  PubMed  CAS  Google Scholar 

  61. Tanaka M, Fuentes ME, Yamaguchi K et al (1999) Embryonic lethality, liver degeneration and impaired NF-κ B activation in IKK-beta-deficient mice. Immunity 10:421–429

    Article  PubMed  CAS  Google Scholar 

  62. Rudolph D, Yeh WC, Wakeham A et al (2000) Severe liver degeneration and lack of NF-κB activation in NEMO/IKKgamma-deficient mice. Genes Dev 14:854–862

    PubMed  CAS  Google Scholar 

  63. Hu Y, Baud V, Delhase M et al (1999) Abnormal morphogenesis but intact IKK activation in mice lacking the IKKalpha subunit of IκB kinase. Science 284:316–320

    Article  PubMed  CAS  Google Scholar 

  64. Takeda K, Takeuchi O, Tsujimura T et al (1999) Limb and skin abnormalities in mice lacking IKKalpha. Science 284:313–316

    Article  PubMed  CAS  Google Scholar 

  65. Luedde T, Assmus U, Wustefeld T et al (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

    PubMed  CAS  Google Scholar 

  66. Luedde T, Beraza N, Kotsikoris V et al (2007) Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 11:119–132

    Article  PubMed  CAS  Google Scholar 

  67. Maeda S, Chang L, Li ZW et al (2003) IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFalpha. Immunity 19:725–737

    Article  PubMed  CAS  Google Scholar 

  68. Pahl HL (1999) Activators and target genes of Rel/NF-κB transcription factors. Oncogene 18:6853–6866

    Article  PubMed  CAS  Google Scholar 

  69. Karin M, Lin A (2002) NFκB at the crossroads of life and death. Nat Immunol 3(227):221–227

    Article  PubMed  CAS  Google Scholar 

  70. Schwabe RF, Brenner DA (2006) Mechanisms of liver injury. I. TNFalpha-induced liver injury: role of IKK JNK and ROS pathways. Am J Physiol Gastrointest. Liver Physiol 290: G583–G589

    Article  CAS  Google Scholar 

  71. De Smaele E, Zazzeroni F, Papa S et al (2001) Induction of GADD45beta by NF-κB downregulates pro-apoptotic JNK signalling. Nature 414:308–313

    Article  PubMed  Google Scholar 

  72. Tang G, Minemoto Y, Dibling B et al (2001) Inhibition of JNK activation through NF-κB target genes. Nature 414:313–317

    Article  PubMed  CAS  Google Scholar 

  73. Chen F, Castranova V, Li Z et al (2003) Inhibitor of nuclear factor κB kinase deficiency enhances oxidative stress and prolongs c-Jun NH2-terminal kinase activation induced by arsenic. Cancer Res 63:7689–7693

    PubMed  CAS  Google Scholar 

  74. Kamata H, Honda S, Maeda S et al (2005) Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120:649–661

    Article  PubMed  CAS  Google Scholar 

  75. Chang L, Kamata H, Solinas G et al (2006) The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover. Cell 124:601–613

    Article  PubMed  CAS  Google Scholar 

  76. Nebreda AR, Porras A (2000) p38 MAP kinases: beyond the stress response. Trends Biochem Sci 25:257–260

    Article  PubMed  CAS  Google Scholar 

  77. Schieven GL (2005) The biology of p38 kinase: a central role in inflammation. Curr Top Med Chem 5:921–928

    Article  PubMed  CAS  Google Scholar 

  78. Heinrichsdorff J, Luedde T, Perdiguero E, Nebreda AR, Pasparakis M (2008) p38 alpha MAPK inhibits JNK activation and collaborates with IκB kinase 2 to prevent endotoxin-induced liver failure. EMBO Rep 9:1048–1054

    Article  PubMed  CAS  Google Scholar 

  79. Jaeschke H (2003) Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol 284:G15–G26

    Google Scholar 

  80. Rudiger HA, Clavien PA (2002) Tumor necrosis factor alpha, but not Fas, mediates hepatocellular apoptosis in the murine ischemic liver. Gastroenterology 122:202–210

    Article  PubMed  CAS  Google Scholar 

  81. Zwacka RM, Zhang Y, Zhou W et al (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

    Article  PubMed  CAS  Google Scholar 

  82. Fan C, Li Q, Ross D, Engelhardt JF (2003) Tyrosine phosphorylation of I κ B alpha activates NF κ B through a redox-regulated and c-Src-dependent mechanism following hypoxia/reoxygenation. J Biol Chem 278: 2072–2080

    Article  PubMed  CAS  Google Scholar 

  83. Fan C, Li Q, Zhang Y et al (2004) IκBalpha and IκBbeta possess injury context-specific functions that uniquely influence hepatic NF-κB induction and inflammation. J Clin Invest 113:746–755

    PubMed  CAS  Google Scholar 

  84. Okuda K (2000) Hepatocellular carcinoma. J Hepatol 32:225–237

    Article  PubMed  CAS  Google Scholar 

  85. Tai DI, Tsai SL, Chang YH et al (2000) Constitutive activation of nuclear factor κB in hepatocellular carcinoma. Cancer 89:2274–2281

    Article  PubMed  CAS  Google Scholar 

  86. Pikarsky E, Porat RM, Stein I et al (2004) NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature 431:461–466

    Article  PubMed  CAS  Google Scholar 

  87. Maeda S, Kamata H, Luo JL et al (2005) IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121:977–990

    Article  PubMed  CAS  Google Scholar 

  88. Mauad TH, van Nieuwkerk CM, Dingemans KP et al (1994) 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 145:1237–1245

    PubMed  CAS  Google Scholar 

  89. Sakurai T, He G, Matsuzawa A et al (2008) Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 14:156–165

    Article  PubMed  CAS  Google Scholar 

  90. Naugler WE, Sakurai T, Kim S et al (2007) Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317:121–124

    Article  PubMed  CAS  Google Scholar 

  91. Bataller R, Brenner DA (2005) Liver fibrosis. J Clin Invest 115:209–218

    PubMed  CAS  Google Scholar 

  92. Friedman SL (2004) Mechanisms of disease: mechanisms of hepatic fibrosis and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol 1:98–105

    Article  PubMed  Google Scholar 

  93. Elsharkawy AM, Wright MC, Hay RT et al (1999) Persistent activation of nuclear factor-κB in cultured rat hepatic stellate cells involves the induction of potentially novel Rel-like factors and prolonged changes in the expression of IκB family proteins. Hepatology 30:761–769

    Article  PubMed  CAS  Google Scholar 

  94. Saile B, DiRocco P, Dudas J et al (2004) IGF-I induces DNA synthesis and apoptosis in rat liver hepatic stellate cells (HSC) but DNA synthesis and proliferation in rat liver myofibroblasts (rMF). Lab Invest 84:1037–1049

    Article  PubMed  CAS  Google Scholar 

  95. Saile B, Matthes N, El Armouche H et al (2001) The bcl, NFκB and p53/p21WAF1 systems are involved in spontaneous apoptosis and in the anti-apoptotic effect of TGF-beta or TNF-alpha on activated hepatic stellate cells. Eur J Cell Biol 80:554–561

    Article  PubMed  CAS  Google Scholar 

  96. Elsharkawy AM, Oakley F, Mann DA (2005) The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis. Apoptosis 10:927–939

    Article  PubMed  CAS  Google Scholar 

  97. Oakley F, Meso M, Iredale JP et al (2005) Inhibition of inhibitor of κB kinases stimulates hepatic stellate cell apoptosis and accelerated recovery from rat liver fibrosis. Gastroenterology 128:108–120

    Article  PubMed  CAS  Google Scholar 

  98. Weber CK, Liptay S, Wirth T et al (2000) Suppression of NF-κB activity by sulfasalazine is mediated by direct inhibition of IκB kinases alpha and beta. Gastroen­terology 119:1209–1218

    Article  PubMed  CAS  Google Scholar 

  99. Seki E, De Minicis S, Osterreicher CH et al (2007) TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med 13:1324–1332

    Article  PubMed  CAS  Google Scholar 

  100. Trautwein C, Tacke F (2003) Treatment of hepatitis B and C virus infection. Dtsch Med Wochenschr 128(Suppl 2): S87–S89

    Google Scholar 

  101. Chirillo P, Falco M, Puri PL et al (1996) Hepatitis B virus pX activates NF-κ B-dependent transcription through a Raf-independent pathway. J Virol 70:641–646

    PubMed  CAS  Google Scholar 

  102. Su F, Schneider RJ (1996) Hepatitis B virus HBx protein activates transcription factor NF-κB by acting on ­multiple cytoplasmic inhibitors of rel-related proteins. J Virol 70:4558–4566

    PubMed  CAS  Google Scholar 

  103. Su F, Theodosis CN, Schneider RJ (2001) Role of NF-κB and myc proteins in apoptosis induced by hepatitis B virus HBx protein. J Virol 75:215–225

    Article  PubMed  CAS  Google Scholar 

  104. Huang IC, Chien CY, Huang CR, Lo SJ (2006) Induction of hepatitis D virus large antigen translocation to the cytoplasm by hepatitis B virus surface antigens correlates with endoplasmic reticulum stress and NF-κB activation. J Gen Virol 87:1715–1723

    Article  PubMed  CAS  Google Scholar 

  105. Cooper A, Tal G, Lider O, Shaul Y (2005) Cytokine induction by the hepatitis B virus capsid in macrophages is facilitated by membrane heparan sulfate and involves TLR2. J Immunol 175:3165–3176

    PubMed  CAS  Google Scholar 

  106. Mann EA, Stanford S, Sherman KE (2006) Prevalence of mutations in hepatitis C virus core protein associated with alteration of NF-κB activation. Virus Res 121:51–57

    Article  PubMed  CAS  Google Scholar 

  107. Tai DI, Tsai SL, Chen YM et al (2000) Activation of nuclear factor κB in hepatitis C virus infection: implications for pathogenesis and hepatocarcinogenesis. Hepatology 31: 656–664

    Article  PubMed  CAS  Google Scholar 

  108. Sato Y, Kato J, Takimoto R et al (2006) Hepatitis C virus core protein promotes proliferation of human hepatoma cells through enhancement of transforming growth factor alpha expression via activation of nuclear factor-κB. Gut 55:1801–1808

    Article  PubMed  CAS  Google Scholar 

  109. Cai D, Yuan M, Frantz DF et al (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-κB. Nat Med 11:183–190

    Article  PubMed  CAS  Google Scholar 

  110. Arkan MC, Hevener AL, Greten FR et al (2005) IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11:191–198

    Article  PubMed  CAS  Google Scholar 

  111. Wunderlich FT, Luedde T, Singer S et al (2008) Hepatic NF-κ B essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis. Proc Natl Acad Sci USA 105:1297–1302

    Article  PubMed  Google Scholar 

  112. Sun B, Karin M (2008) NF-κB signaling, liver disease and hepatoprotective agents. Oncogene 27: 6228–6244

    Article  PubMed  CAS  Google Scholar 

  113. Karin M, Yamamoto Y, Wang QM (2004) The IKK NF-κ B system: a treasure trove for drug development. Nat Rev Drug Discov 3:17–26

    Article  PubMed  CAS  Google Scholar 

  114. Greten FR, Arkan MC, Bollrath J et al (2007) NF-κB is a negative regulator of IL-1beta secretion as revealed by genetic and pharmacological inhibition of IKKbeta. Cell 130:918–931

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Work in the laboratory of T.L. is supported by starting grants from the European Research Council (No. 208237), the German Research Foundation (SFB/TRR 57), and the Interdisciplinary Centre for Clinical Research “BIOMAT.” within the Faculty of Medicine at RWTH Aachen University (to T.L. and C.T.). Work in the laboratory of C.T. is supported by the German Research Foundation (SFB/TRR 57)/(SFB 542) and the German Cancer Foundation.

Author information

Authors and Affiliations

  1. Medical Department III, University Hospital RWTH Aachen, Pauwelsstraße, 30, 52074, Aachen, Germany

    Tom Luedde & Christian Trautwein

Authors
  1. Tom Luedde
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christian Trautwein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tom Luedde .

Editor information

Editors and Affiliations

  1. Inselspital, Universität Bern, Murtenstr. 35, Bern, 3010, Switzerland

    Jean-Francois Dufour

  2. Klinik für Viszeral- und, Universitätsspital Zürich, Rämistr. 100, Zürich, 8091, Switzerland

    Pierre-Alain Clavien

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Luedde, T., Trautwein, C. (2010). NF-κB. In: Dufour, JF., Clavien, PA. (eds) Signaling Pathways in Liver Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00150-5_13

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-00150-5_13

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-00149-9

  • Online ISBN: 978-3-642-00150-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation