Skip to main content
PMC home page
Journal of Cellular and Molecular Medicine logoLink to Journal of Cellular and Molecular Medicine
. 2007 May 1;8(4):445–454. doi: 10.1111/j.1582-4934.2004.tb00469.x

Dissection of the multiple mechanisms of TNF‐α‐induced apoptosis in liver injury

Wen‐Xing Ding 1, Xiao‐Ming Yin 1,✉
PMCID: PMC6740227  PMID: 15601573

Abstract

Tumor necrosis factor (TNF)‐α‐induced hepatocyte apoptosis is implicated in a wide range of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion liver injury, and fulminant hepatic failure. TNF‐α exerts a variety of effects that are mediated mainly by TNF‐receptor 1 (TNF‐R1) in cell death. The activation of TNF‐R1 leads to the activation of multiple apoptotic pathways involving the activation of the pro‐death Bcl‐2 family proteins, reactive oxygen species, C‐Jun NH2‐terminal kinase, cathepsin B, acidic sphingomyelinase and neutral sphingomyelinase. These pathways are closely interlinked and mainly act on mitochondria, which release the apoptogenic factors and other events, resulting in apoptosis. This article reviews the recent progress in the molecular mechanisms of TNF‐α‐induced apoptosis in hepatocytes, and discusses how these molecular findings are shaping our understanding of the pathogenesis of liver diseases and our strategy to develop novel therapeutics.

Keywords: apoptosis, mitochondria, Bcl‐2 family proteins, TNF‐α, reactive oxygen species, liver injury

References

  • 1. Yoon J.H., Gores G.J., Death receptor‐mediated apoptosis and the liver, J. Hepatol., 37: 400–410, 2002. [DOI] [PubMed] [Google Scholar]
  • 2. Yin X.M., Ding W.X., Death receptor activation‐induced hepatocyte apoptosis and liver injury, Curr. Mol. Med., 3: 491–508, 2003. [DOI] [PubMed] [Google Scholar]
  • 3. Wang H., Czura C.J., Tracey K.J., Tumor necrosis factor In: The Cytokine Handbook, 4th Edition (Eds Thomson A.W. & Lotze M.T.). Elsevier Science Ltd, London . 2003. pp. 837–860. [Google Scholar]
  • 4. Muto Y., Nouri‐Aria K.T., Meager A., Alexander G.J., Eddleston A.L., Williams, R. , Enhanced tumour necrosis factor and interleukin‐1 in fulminant hepatic failure, Lancet 9;2: 72–74, 1988. [DOI] [PubMed] [Google Scholar]
  • 5. Zylberberg H., Rimaniol A.C., Pol S., Masson A., De Groote D., Berthelot P., Bach J.F., Brechot C., Zavala F., Soluble tumor necrosis factor receptors in chronic chepatitis C: a correlation with histological fibrosis and activity, J. Hepatol., 30: 185–191, 1999. [DOI] [PubMed] [Google Scholar]
  • 6. Yin M., Wheller M.D., Kono H., Bradford B.U., Gallucci R.M., Luster M.I., Thurman R.G., Essential role of tumor necrosis factor alpha in alcohol‐induced liver injury in mice. Gastroenterology, 117: 942–952, 1999. [DOI] [PubMed] [Google Scholar]
  • 7. Bird G.L., Sheron N., Goka A.K., Alexander G.J., Williams R.S., Increased plasma tumor necrosis factor in severe alcoholic hepatitis, Ann. Intern. Med., 112: 917–920, 1990. [DOI] [PubMed] [Google Scholar]
  • 8. McClain C.J., Cohen D.A., Increased tumor necrosis factor production by monocytes in alcoholic hepatitis, Hepatology, 9: 349–51, 1989. [DOI] [PubMed] [Google Scholar]
  • 9. Grove J., Daly A.K., Bassendine M.F., Day C.P., Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis, Hepatology, 26: 143–146, 1997. [DOI] [PubMed] [Google Scholar]
  • 10. Rudiger H.A., Clavien P.A., Tumor necrosis factor alpha, but not Fas, mediates hepatocellular apoptosis in the murine ischemic liver, Gastroenterology, 122: 202–210, 2002. [DOI] [PubMed] [Google Scholar]
  • 11. Micheau O., Tschopp J. Induction of TNF receptor I‐mediated apoptosis via two sequential signaling complexes, Cell, 141: 181–190, 2003. [DOI] [PubMed] [Google Scholar]
  • 12. Ding W.X., Ni H.M., DiFrancesca D., Stolz D.B., Yin X.M., Bid‐dependent generation of oxygen radicals promotes death receptor activation‐induced apoptosis in murine hepatocytes, Hepatology, 40: 403–413, 2004. [DOI] [PubMed] [Google Scholar]
  • 13. Kim T.H., Zhao Y., Ding W.X., Shin J.N., He X., Seo Y.W., Chen J., Rabinowich H., Amoscato A.A., Yin X.M., Bid‐cardiolipin interaction at mitochondrial contact site contributes to mitochondrial cristae reorganization and cytochrome C release, Mol. Biol. Cell, 15: 3061–3072, 2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Bradham C.A., Qian T., Streetz K., Trautwein C., Brenner D.A., Lemasters J.J., The mitochondrial permeability transition is required for tumor necrosis factor alpha‐mediated apoptosis and cytochrome c release, Mol. Cell Biol., 18: 6353–6364, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. Zhao Y., Ding W.X., Qian T., Watkins S., Lemasters J.J., Yin X.M., Bid activates multiple mitochondrial apoptotic mechanisms in primary hepatocytes after death receptor engagement, Gastroenterology, 125:854–867, 2003. [DOI] [PubMed] [Google Scholar]
  • 16. Lemasters J.J., Nieminen A.L., Qian T., Trost L.C., Elmore S.P., Nishimura Y., Crowe R.A., Cascio W.E., Bradham C.A., Brenner D.A., Herman B., The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy, Biochim. Biophys. Acta, 1366: 177–196, 1998. [DOI] [PubMed] [Google Scholar]
  • 17. Soriano M.E., Nicolosi L. Bernardi P., Desensitization of the permeability transition pore by cyclosporin a prevents activation of the mitochondrial apoptotic pathway and liver damage by tumor necrosis factor‐alpha, J. Biol. Chem., 279: 36803–36808, 2004. [DOI] [PubMed] [Google Scholar]
  • 18. Jiang X., Wang X., Cytochrome c promotes caspase‐9 activation by inducing nucleotide binding to Apaf‐1, J. Biol. Chem., 275: 31199–31203, 2000. [DOI] [PubMed] [Google Scholar]
  • 19. Li S., Zhao Y., He X., Kim T.H., Kuharsky D.K., Rabinowich H., Chen J., Du C., Yin X.M., Relief of extrinsic pathway inhibition by the Bid‐dependent mitochondrial release of Smac in Fas‐mediated hepatocyte apoptosis, J. Biol. Chem., 277: 26912–26920, 2002. [DOI] [PubMed] [Google Scholar]
  • 20. Du C., Fang M., Li Y., Li L., Wang X., Smac, a mitochondrial protein that promotes cytochrome c‐dependent caspase activatin by eliminating IAP inhibition, Cell, 102: 33–42, 2000. [DOI] [PubMed] [Google Scholar]
  • 21. Zhao Y., Li S., Childs E.E., Kuharsky D.K., Yin X.M. Activation of pro‐death Bcl‐2 family proteins and mitochondria apoptosis pathway in tumor necrosis factoralpha‐induced liver injury, J. Biol. Chem., 276: 27432–27440, 2001. [DOI] [PubMed] [Google Scholar]
  • 22. Wei M.C., Zong W.X., Cheng H., Lindsten T., Panoutsakopoulou V., Ross A.J., Roth K.A., MacGregor G.R., Thompson C.B., Korsmeyer S.J., Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death, Science, 292: 727–730, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Garcia‐Ruiz C., Colell A., Mari M., Morales A., Calvo M., Enrich C., Fernandez‐Checa J.C., Defective TNF‐alpha‐mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice, J. Clin. Invest., 111: 197–208, 2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Nechushtan A., Smith C.L., Hsu Y.T., Youle R.J., Conformation of the Bax C‐terminus regulates subcellular location and cell death, EMBO J., 18: 2330–2341, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Nagai H., Matsumaru K., Feng G., Kaplowitz N., Reduced glutathione depletion causes necrosis and sensitization to tumor necrosis factor‐alpha‐induced apoptosis in culturedmouse hepatocytes, Hepatology, 36: 55–64, 2002. [DOI] [PubMed] [Google Scholar]
  • 26. Matsumaru K., Ji C., Kaplowitz N., Mechanisms for sensitization to TNF‐induced apoptosis by acute glutathione depletion in murine hepatocytes, Hepatology, 37: 1425–1434, 2003. [DOI] [PubMed] [Google Scholar]
  • 27. Okuyama H., Nakamura H., Shimahara Y., Araya S., Kawada N., Yamaoka Y., Yodoi J., Overexpression of thioredoxin prevents acute hepatitis caused by thioacetamide or lipopolyaccharide in mice, Hepatology, 37: 1015–1025, 2003. [DOI] [PubMed] [Google Scholar]
  • 28. Hockenbery D.M., Oltavi Z.N., Yin X.M., Milliman C.L., Korsmeyer S.J., Bcl‐2 functions in an antioxidant pathway to prevent apoptosis, Cell, 75: 241–251, 1993. [DOI] [PubMed] [Google Scholar]
  • 29. Hochman A., Sternin H., Gorodin S., Korsmeyer S., Ziv I., Melamed E., Offen D., Enhanced oxidative stress and altered antioxidants in brains of Bcl‐2‐deficient mice, J. Neurochem., 71: 741–748, 1998. [DOI] [PubMed] [Google Scholar]
  • 30. Xiang J., Chao D. T., Korsmeyer S.J., BAX‐induced cell death may not require interleukin 1 beta‐converting enzyme‐like proteases, Proc. Natl. Acad. Sci. USA, 93: 14559–14563, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Chang L., Karin M., Mammalian MAP kinase signalling cascades, Nature, 410: 37–40, 2001. [DOI] [PubMed] [Google Scholar]
  • 32. Liu, Z.G. , Adding facets to TNF signaling. The JNK angle, Mol. Cell., 12: 795–796, 2003. [DOI] [PubMed] [Google Scholar]
  • 33. Liu H., Lo C.R., Czaja M.J., NF‐kappaB inhibition sensitizes hepatocytes to TNF‐induced apoptosis through a sustained activation of JNK and c‐Jun, Hepatology, 35: 772–778, 2002. [DOI] [PubMed] [Google Scholar]
  • 34. Schwabe R.F., Uchinami H., Qian T., Bennett B.L., Lemasters J.J., Brenner D.A., Differential requirement for c‐Jun NH2‐terminal kinase in TNFalpha‐ and Fasmediated apoptosis in hepatocytes, FASEB J., 18:720–722, 2004. [DOI] [PubMed] [Google Scholar]
  • 35. Deng Y., Ren X., Yang L., Lin Y., Wu X., A JNK‐dependent pathway is required for TNFalpha‐induced apoptosis, Cell, 115: 61–70, 2003. [DOI] [PubMed] [Google Scholar]
  • 36. Lei K., Nimnual A., Zong W.X., Kennedy N.J., Flavell R.A., Thompson C.B., Bar‐Sagi D., Davis R.J., The Bax subfamily of Bc12‐related proteins is essential for apoptotic signal transduction by c‐Jun NH(2)‐terminal kinase, Mol. Cell. Biol., 22: 4929–4942, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Rowan, A.D. , Mason, P. , Mach, L. , and Mort, J.S. , Rat procathepsin B. Proteolytic processing to the mature form in vitro , J. Biol. Chem., 267: 15993–15999, 1992. [PubMed] [Google Scholar]
  • 38. Guicciardi M.E., Deussing J., Miyoshi H., Bronk S.F., Svingen P.A., Peters C., Kaufmann S.H., Gores G.J., Cathepsin B contributes to TNF‐alpha‐mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c. J. Clin. Invest., 106: 1127–1137, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Guicciardi M.E., Miyoshi H., Bronk S.F., Gores G.J., Cathepsin B knockout mice are resistant to tumor necrosis factor‐alpha‐mediated hepatocyte apoptosis and liver injury: implications for therapeutic applications, Am. J. Pathol., 159: 2045–2054, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Werneburg N., Guicciardi M.E., Yin X.M., Gores G.J., TNF‐alpha‐mediated lysosomal permeabilization is FAN and caspase 8/Bid dependent, Am. J. Physiol. Gastrointest. Liver Physiol., 287:G436–443, 2004. [DOI] [PubMed] [Google Scholar]
  • 41. Merrill A.H. Jr., Lingrell S., Wang E., Nikolova‐Karakashian M., Vales T.R., Vance D.E., Sphingolipid biosynthesis de novo by rat hepatocytes in culture. Ceramide and sphingomyelin are associated with, but not required for, very low density lipoprotein secretion, J. Biol. Chem., 270: 13834–13841, 1995. [DOI] [PubMed] [Google Scholar]
  • 42. Segui B., Cuvillier O., Adam‐Klages S., Garcia V., Malagarie‐Cazenave S., Leveque S., Caspar‐Bauguil S., Coudert J., Salvayre R., Kronke M., Levade T., Involvement of FAN in TNF‐induced apoptosis, J. Clin. Invest., 108: 143–145, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Malagarie‐Cazenave S., Segui B., Leveque S., Garcia V., Carpentier S., Altie M.F., Brouchet A., Gouaze V., Andrieu‐Abadie N., Barreira Y., Benoist H., Levade T., Role of FAN in tumor necrosis factor‐alpha and lipopolysaccharide‐induced interleukin‐6 secretion and lethality in D‐glactosamine‐sensitized mice, J. Biol. Chem., 279: 18648–18655, 2004. [DOI] [PubMed] [Google Scholar]
  • 44. Arora A.S., Jones B.J., Patel T.C., Bronk S.F., Gores G.J., Ceramide induces hepatocyte cell death through disruption of mitochondrial function in the rat, Hepatology, 25: 958–63, 1997. [DOI] [PubMed] [Google Scholar]
  • 45. Mari M., Colell A., Morales A., Paneda C., Varela‐Nieto I., Garcia‐Ruiz C., Fernandez‐Checa J.C., Acidic sphingomyelinase downregulates the liver‐specific methionine adenosyltransferase 1A, contributing to tumor necrosis factor‐induced lethal hepatitis, J. Clin. Invest., 113: 895–904, 2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46. Arvelo M.B., Cooper J.T., Longo C., Daniel S., Grey S.T., Mahiou J., Czismadia E., Abu‐Jawdeh G., Ferran C., A20 protects mice from D‐galactosamine/lipopolysaccharide acute toxic lethal hepatitis, Hepatology, 35: 535–543, 2002. [DOI] [PubMed] [Google Scholar]
  • 47. Hatano E., Bennett B.L., Manning A.M., Qian T., Lemasters J.J., Brenner D.A., NF‐kappaB stimulates inducible nitric oxide synthase to protect mouse hepatocytes from TNF‐alpha‐ and Fas‐mediated apoptosis, Gastroenterology, 120: 1251–1262, 2001. [DOI] [PubMed] [Google Scholar]
  • 48. Kunstle G., Leist M., Uhlig S., Revesz L., Feifel R., MacKenzie A., Wendel A., ICE‐protease inhibitors block murine liver injury and apoptosis caused by CD95 or by TNF‐alpha, Immunol. Lett., 55: 5–10, 1997. [DOI] [PubMed] [Google Scholar]
  • 49. Maeda S., Chang L., Li Z.W., Luo J.L., Leffert H., Karin M., IKKbeta is required for prevention of apoptosis mediated by cell‐bound but not by circulating TNFalpha, Immunity, 19: 725–737, 2003. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Cellular and Molecular Medicine are provided here courtesy of Blackwell Publishing

RESOURCES