TNF/TNF Receptor 1-Mediated Apoptosis in Hepatocytes

  • Hyun-Ae Eum
  • Timothy R. Billiar
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 691)


Tumor necrosis factor (TNF)-alpha has been implicated in the induction of hepatocyte apoptosis in a variety of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury, and cancer. The binding of TNF to TNF receptor 1 (TNFR1) induces two simultaneous pathways, one leading to cell survival through NF-κB activation and the other cell death via apoptosis. How these pathways are regulated is poorly understood in hepatocytes. Emerging data suggest that there are often aspects of TNFR1-initiate signaling that are unique to hepatocyte. Here we summarize the past and present knowledge of the TNF/TNFR1 system in the liver.


Tumor Necrosis Factor Tumor Necrosis Factor Receptor Death Domain Alcoholic Hepatitis Hepatocyte Apoptosis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Leist M, Gantner F, Nauman H et al (1997) Tumor necrosis factor-induced apoptosis during the poisoning of mice with hepatotoxins. Gastroenterology 112:923–934CrossRefPubMedGoogle Scholar
  2. 2.
    Bradham CA, Plumpe J, Manns MP et al (1998) Mechanisms of hepatic toxicity. I. TNF -induced liver injury. Am J Physiol 275:G387–392PubMedGoogle Scholar
  3. 3.
    Wajant H, Pfizenmaier K, Scheurich P (2003) Tumor necrosis factor signaling. Cell Death Differ 10:45–65CrossRefPubMedGoogle Scholar
  4. 4.
    Kimura T, Sakaida I, Terai S et al (1997) Inhibition of tumor necrosis factor-alpha production retards liver regeneration after partial hepatectomy in rats. Biochem Biophys Res Commun 231(3):557–560CrossRefPubMedGoogle Scholar
  5. 5.
    Garcia-Ruiz C, Fernández-Checa JC (2007) Redox regulation of hepatocyte apoptosis. J Gastroenterol Hepatol 22:S38–42CrossRefPubMedGoogle Scholar
  6. 6.
    Patel T (2000) Apoptosis in hepatic pathophysiology. Clin liver Dis 4:295–317CrossRefPubMedGoogle Scholar
  7. 7.
    Hsu H, Huang J, Shu HB et al (1996) TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity 4:387–396CrossRefPubMedGoogle Scholar
  8. 8.
    Hsu H, Shu HB, Pan MG et al (1996) TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 84:299–308CrossRefPubMedGoogle Scholar
  9. 9.
    Boldin MP, Goncharov TM, Goltsev YV et al (1996) Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell 85:803–815CrossRefPubMedGoogle Scholar
  10. 10.
    Muzio M, Chinnaiyan AM, Kischkel FC et al (1996) FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85:817–827CrossRefPubMedGoogle Scholar
  11. 11.
    Micheau O, Tschopp J (2003) Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114:181–190CrossRefPubMedGoogle Scholar
  12. 12.
    Muppidi JR, Tschopp J, Siegel RM (2004) Life and death decisions: secondary complexes and lipid rafts in TNF receptor family signal transduction. immunity 21:461–465CrossRefPubMedGoogle Scholar
  13. 13.
    Schneider-Brachert W, Tchikov V, Neumeyer J et al (2004) Compartmentalization of TNF receptor 1 signaling: internalized TNF receptosomes as death signaling vesicles. Immunity 21:415–428CrossRefPubMedGoogle Scholar
  14. 14.
    Wang CY, Mayo MW, Korneluk RG et al (1998) NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase 8 activation. Science 281:1680–1683CrossRefPubMedGoogle Scholar
  15. 15.
    Imose M, Nagaki M, Naiki T et al (2003) Inhibition of nuclear factor kappaB and phosphatidylinositol 3-kinase/Akt is essential for massive hepatocyte apoptosis induced by tumor necrosis factor alpha in mice. Liver Int. 23(5):386–396CrossRefPubMedGoogle Scholar
  16. 16.
    Nagaki M, Moriwaki H (2002) How are hepatocytes sensitized to apoptosis?. J Gastroenterol 37(12):1094–1096CrossRefPubMedGoogle Scholar
  17. 17.
    Wang Y, Singh R, Lefkowitch JH et al (2006) Tumor necrosis factor-induced toxic liver injury results from JNK2 dependent activation of caspase-8 and the mitochondrial death pathway. J Biol Chem 281(22):15258–15267CrossRefPubMedGoogle Scholar
  18. 18.
    Tzeng E, Billiar TR, Williams DL et al (1998) Adenovirus-mediated inducible nitric oxide synthase gene transfer inhibits hepatocyte apoptosis. Surgery 124(2):278–283PubMedGoogle Scholar
  19. 19.
    Kim YM, Kim TH, Chung HT et al (2000) Nitric oxide prevents tumor necrosis factor alpha-induced rat hepatocyte apoptosis by the interruption of mitochondrial apoptotic signaling through S-nitrosylation of caspase-8. Hepatology 32:770–778CrossRefPubMedGoogle Scholar
  20. 20.
    Kim YM, Talanian RV, Billiar TR (1997) Nitric oxide inhibits apoptosis by preventing increases in caspase-3-like activity via two distinct mechanisms. J Biol Chem 272(49):31138–31148CrossRefPubMedGoogle Scholar
  21. 21.
    Kim PK, Wang Y, Gambotto A et al (2002) Hepatocyte Fas-associating death domain protein/mediator of receptor-induced toxicity (FADD/MORT1) levels increase in response to pro-apoptotic stimuli. J Biol Chem 277(41):38855–38862CrossRefPubMedGoogle Scholar
  22. 22.
    Wang Y, Kim PK, Peng X et al (2006) Cyclic AMP and cyclic GMP suppress TNF alpha-induced hepatocyte apoptosis by inhibiting FADD up-regulation via a protein kinase A-dependent pathway. Apoptosis 11:441–451CrossRefPubMedGoogle Scholar
  23. 23.
    Zhang X, Vallabhaneni R, Loughran PA et al (2008) Changes in FADD levels, distribution, and phosphorylation in TNFalpha-induced apoptosis in hepatocytes is caspase-3, caspase-8 and BID dependent. Apoptosis 13(8):983–992CrossRefPubMedGoogle Scholar
  24. 24.
    Li H, Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94:491–501CrossRefPubMedGoogle Scholar
  25. 25.
    Li S, Zhao Y, He X et al (2002) Relief of extrinsic pathway inhibition by the Bid-dependent mitochondrial release of Smac in Fas-mediated hepatocyte apoptosis. J Biol Chem 277:26912–26920CrossRefPubMedGoogle Scholar
  26. 26.
    Yin XM, Wang K, Gross A et al (1999) Bid-defocoent mice are resistant to Fas-induced hepatocellular apoptosis. Nature 400:886–891CrossRefPubMedGoogle Scholar
  27. 27.
    Ding WX, Ni HM (2004) Bid dependent generation of oxygen radicals promotes death receptor activation-induced apoptosis in murine hepatocyte. Hepatology 40:403–413CrossRefPubMedGoogle Scholar
  28. 28.
    Zhao Y, Ding WX, Qian T et al (2003) Bid activates multiple mitochondrial apoptotic mechanisms in primary hepatocytes after death receptor engagement Gastroenterology 125:854–867CrossRefPubMedGoogle Scholar
  29. 29.
    Zhao Y, Li S, Childs EE et al (2001) Activation of pro-death Bcl-2 family proteins and mitochondria apoptosis pathway in tumor necrosis factor-α-induced liver injury. J Biol Chem 276:27432–27440CrossRefPubMedGoogle Scholar
  30. 30.
    Bradley JR, Thiru S, Pober JS (1995) Disparate localization of 55-kd and 75-kd tumor necrosis factor receptors in human endothelial cells. Am J Pathol 146:27–32PubMedGoogle Scholar
  31. 31.
    Jones SJ, Ledgerwood EC, Prins JB et al (1999) TNF recruits TRADD to the plasma membrane but not the trans-Golgi network, the principal subcellular location of TNFR1. J Immunol 162:1042–1048PubMedGoogle Scholar
  32. 32.
    Cottin V, Doan JE, Riches DW (2002) Restricted localization of the TNF receptor CD120a to lipid rafts: a novel role for the death domain. J Immunol 168:4095–4102PubMedGoogle Scholar
  33. 33.
    Nanji AA (1998) Apoptosis and alcoholic liver disease. Semin Liver Dis 18(2):187–190CrossRefPubMedGoogle Scholar
  34. 34.
    Bird GL, Sheron N, Goka AK et al (1990) Increased plasma tumor necrosis factor in severe alcoholic hepatitis. Ann Intern Med 112:917–920PubMedGoogle Scholar
  35. 35.
    Spahr L, Giostra E, Frossard JL et al (2004) Soluble TNF-R1, but not tumor necrosis factor alpha, predicts the 3-month mortality in patients with alcoholic hepatitis. J Hepatol 41:229–234CrossRefPubMedGoogle Scholar
  36. 36.
    Torre F, Rossol S, Pelli N et al (2004) Kinetics of soluble tumour necrosis factor (TNF)-alpha receptors and cytokines in the early phase of treatment for chronic hepatitis C: comparison between interferon (IFN)-alpha alone, IFN-alpha plus amantadine or plus ribavirin. Clin Exp Immunol 136:507–512CrossRefPubMedGoogle Scholar
  37. 37.
    Fang JW, Shen WW, Meager A et al (1996) Activation of the tumor necrosis factor-alpha system in the liver in chronic hepatitis B virus infection. Am J Gastroenterol 91:748–753PubMedGoogle Scholar
  38. 38.
    Grenz A, Schenk M, Zipfel A et al (2000) TNF-alpha and its receptors mediate graft rejection and loss after liver transplantation. Clin Chem Lab Med 38(11):1183–1185CrossRefPubMedGoogle Scholar
  39. 39.
    Imagawa DK, Millis JM, Olthoff KM et al (1990) The role of tumor necrosis factor in allograft rejection. I. Evidence that elevated levels of tumor necrosis factor-alpha predict rejection following orthotopic liver transplantation. Transplantation 50(2):219–225CrossRefPubMedGoogle Scholar
  40. 40.
    Streetz K, Leifeld L, Grundmann D et al (2000) Tumor necrosis factor alpha in the pathogenesis of human and murine fulminant hepatic failure. Gastroenterology 119:446–460CrossRefPubMedGoogle Scholar
  41. 41.
    Rudiger HA, Clavien PA (2002) Tumor necrosis factor alpha, but not Fas, mediates hepatocellular apoptosis in the murine ischemic liver. Gastroenterology 122:202–210CrossRefPubMedGoogle Scholar
  42. 42.
    Gehring S, Dickson EM, San Martin ME (2006) Kupffer cells abrogate cholestatic liver injury in mice. Gastroenterology 130(3):810–822CrossRefPubMedGoogle Scholar
  43. 43.
    Yamada Y, Webber EM, Kirillova I et al (1998) Analysis of liver regeneration in mice lacking type 1 or type 2 tumor necrosis factor receptor: requirement for type 1 but not type 2 receptor. Hepatology 28:959–970CrossRefPubMedGoogle Scholar
  44. 44.
    Mohammed FF, Smookler DS, Taylor SE et al (2004) Abnormal TNF activity in Timp3-/- mice leads to chronic hepatic inflammation and failure of liver regeneration. Nat Genet 36:969–977CrossRefPubMedGoogle Scholar
  45. 45.
    Conzelmann LO, Zhong Z, Thurman R et al (2002) Role of TNFR1-receptors in graft injury and regeneration after liver transplantation in knockout mice. Gastroenterology 123( Suppl):87Google Scholar
  46. 46.
    Diehl AM (2000) Cytokine regulation of liver injury and repair. Immunol Rev 174:160–171CrossRefPubMedGoogle Scholar
  47. 47.
    Fausto N (2004) Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology 39:1477–1487CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of SurgeryF-1200 PUH, University of PittsburghPittsburghUSA

Personalised recommendations