Role of caspase-1 subfamily in cytotoxic cytokine-induced oligodendrocyte cell death

  • S. Hisahara
  • R. Takano
  • S. Shoji
  • H. Okano
  • M. Miura
Conference paper


Oligodendrocytes are myelin forming cells in mammalian central nervous system. About 50% of oligodendrocytes (OLGs) undergo cell death in normal development. In addition, OLG cell deaths have been observed in demyelinating diseases including multiple sclerosis (MS). Clinical observations and in vitro cell culture studies have suggested that cytokines mediate OLG cell damage in multiple sclerosis (MS). Among the cytokines, tumor necrosis factor (TNF) is thought to be one of the mediators responsible for the damage of OLGs in MS. The administration of TNF-α to primary cultures of OLGs induced DNA fragmentation, and significantly decreased the number of live OLGs. Chemical inhibitors Ac-YVAD-CHO (a specific inhibitor of caspase-1 (ICE)-like proteases) enhanced the survival of TNF-α treated OLGs better than Ac-DEVD-CHO (a specific inhibitor of caspase-3 (CPP32)-like proteases). These results indicate that caspase-1-mediated celldeath pathway are activated in TNF-induced OLG cell death. Caspase-11 is involved in activation of caspase-1. Oligodendrocytes from caspase-11-deficient mice are partially resistant to TNF-induced OLG cell death. Our results suggest that the inhibition of caspase-1 sufamily may be a novel therapeutic approach to treat MS.


Multiple Sclerosis Tumor Necrosis Factor Receptor Prevent Cell Death Caspase Family Inflammatory Demyelinating Disease 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Alnemri E.S., Livingston D.J., Nicholson D.W., Salvesen G, Thornberry N.A., Wong W.W., Yuan J (1996) Human ICE/CED-3 protease nomenclature. Cell 87: 171PubMedCrossRefGoogle Scholar
  2. Boldin M.P., Mett I.L., Varfolomeev E.E., Chumakov I, Shemer-Avni Y, Camonis J.H., Wallach D (1995) Self-association of the “death domains” of the p55 tumor necrosis factor (TNF) receptor and Fas/APOI prompts signaling for TNF and Fas/APOI effects. J Biol Chem 270: 387–391PubMedCrossRefGoogle Scholar
  3. Boldin M.P., Goncharov T.M., Goltsev Y.V., Wallach D (1996) Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptorinduced cell death. Cell 85: 803–815PubMedCrossRefGoogle Scholar
  4. Chinnaiyan A.M., Tepper C.G., Seldin M.F., O’Rourke K, Kischkel F.C., Hellbardt S, Krammer P.H., Peter M.E., Dixit V.M. (1996) FADD/MORT1 is a common mediator of CD95 (Fas/APO-1) and tumor necrosis factor receptor-induced apoptosis. J Biol Chem 271: 4961–4965PubMedCrossRefGoogle Scholar
  5. Dolle R.E., Hoyer D, Prasad C.V., Schmidt S.J., Helaszek C.T., Miller R.E., Ator M.A. (1994) P1 aspartate-based peptide a-((2,6-dichlorobenzoyl)oxy)methyl ketones as potent time-dependent inhibitors of interleukin-1β-converting enzyme. J Med Chem 37:563–564PubMedCrossRefGoogle Scholar
  6. Dopp J.M., Makenzie-Graham A, Otero G.C., Merrill J.E. (1997) Differential expression, cytokine modulation, and specific functions of type-1 and type-2 tumor necrosis factor receptors in rat glia. J Neuroimmnol 75: 104–112CrossRefGoogle Scholar
  7. Dowling P, Husar W, Menonna J, Donnenfeld H, Cook S, Sidhu M (1997) Cell death and birth in multiple sclerosis brain. J Neurol Sci 149: 1–11PubMedCrossRefGoogle Scholar
  8. D’Souza S, Alinauskas K, McCrea E, Goodyer C, Antel J.P. (1995) Differential susceptibility of human CNS-derived cell populations to TNF-dependent and independent immune-mediated injury. J Neurosci 15: 7293–7300Google Scholar
  9. Genain C.P., Roberts T, Davis R.L., Nguyen M.H., Uccelli A, Faulds D, Li Y, Hedgpeth J, Hauser S.L. (1995) Prevention of autoimmune demyelination in non-human primates by a cAMP-specific phosphodiesterase inhibitor. Proc Natl Acad Sci USA 92: 3601–3605PubMedCrossRefGoogle Scholar
  10. Hisahara S, Shoji S, Okano H, Miura M (1997) ICE/CED-3 family executes oligodendrocyte apoptosis by tumor necrosis factor. J Neurochem 69: 10–20PubMedCrossRefGoogle Scholar
  11. Hsu H, Xiong J, Goeddel D.V. (1995) The TNF receptor I-associated protein TRADD signals cell death and NF-KB activation. Cell 81: 495–504PubMedCrossRefGoogle Scholar
  12. Hsu H, Shu H.B., Pan M.G., Goeddel D.V. (1996) TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 84: 299–308PubMedCrossRefGoogle Scholar
  13. Itoh N, Nagata S (1993) A novel protein domain required for apoptosis. Mutational analysis of human Fas antigen. J Biol Chem 268: 10932–10937PubMedGoogle Scholar
  14. Medema J.P., Scaffidi C, Kischkel F.C., Shevchenko A, Mann M, Krammer P.H., Peter M.E. (1997) FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). EMBO J 16: 2794–2804PubMedCrossRefGoogle Scholar
  15. Miura M, Zhu H, Rotello R (1993) Induction of apoptosis in fibroblasts by IL-1βconverting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3. Cell 75: 653–660PubMedCrossRefGoogle Scholar
  16. Miura M, Friedlander R.M., Yuan J (1995) Tumor necrosis factor-induced apoptosis is mediated by a CrmA-sensitive cell death pathway. Proc Natl Acad Sci USA 92: 8318–8322PubMedCrossRefGoogle Scholar
  17. Muzio M, Chinnaiyan A.M., Kischkel F.C., O’Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz J.D., Zhang M, Gentz R, Mann M, Krammer P.H., Peter M.E., Dixit V.M. (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: 817–827PubMedCrossRefGoogle Scholar
  18. Pender M.P., Nguyen K.B., McCombe P.A., Kerr J.F.R. (1991) Apoptosis in the nervous system in experimental allergic encephalomyelitis. J Neurol Sci 104: 81–87PubMedCrossRefGoogle Scholar
  19. Power M, Mitchell D, Lederman J, Buckmeier J, Zamvil S, Graham M, Ruddle N, Steinman L (1990) Lymphotoxin and tumor necrosis factor-alpha production by myelin basic protein-specific T cell clones correlates with encephalitogenicity. Int Immunol 2: 539–544CrossRefGoogle Scholar
  20. Probert L, Akassoglou K, Pasparakis M, Kontogeordos G, Kollias G (1995) Spontaneous inflammatory demyelinating disease in transgenic mice showing central nervous system-specific expression of tumor necrosis factor alfha. Proc Natl Acad Sci USA 92: 11294–11298PubMedCrossRefGoogle Scholar
  21. Ray C.A., Black R.A., Kronheim S.R., Greenstreet T.A., Sleath P.R., Salvesen G.S., Pickup D.J. (1992) Viral inhibition of inflammation: cowpox virus encodes an inhibitor of the interleukin-1β converting enzyme. Cell 69: 597–604PubMedCrossRefGoogle Scholar
  22. Ruddle N, Bergman C, McGrath K, Lingenheld E, Grunnet M, Padula S, Clark R (1990) An antibody tolymphotoxin and tumor necrosis factor prevents transfer to experimental allergic encephalomyelitis. J Exp Med 172: 1193–1200PubMedCrossRefGoogle Scholar
  23. Selmaj K.W., Raine C.S. (1988) Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro. Ann Neurol 23: 339–346PubMedCrossRefGoogle Scholar
  24. Selmaj K, Raine C, Canella B, Brosnan C (1991a) Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions. J Clin Inv 87: 949–954CrossRefGoogle Scholar
  25. Selmaj K, Raine C, Cross A (1991b) Anti-tumor necrosis factor therapy abrogates autoimmune demyelination. Ann Neurol 30: 694–700PubMedCrossRefGoogle Scholar
  26. Tartaglia L.A., Ayres T.M., Wong G.H., Goeddel D.V. (1993) A novel domain within the 55kd TNF receptor signals cell death. Cell 74: 845–853PubMedCrossRefGoogle Scholar
  27. Tewari M, Dixit V.M. (1995) Fas- and tumor necrosis factor-induced apoptosis is inhibited by the poxvirus crmA gene product. J Biol Chem 270: 3255–3260PubMedCrossRefGoogle Scholar
  28. Thornberry N.A., Rano T.A., Peterson E.P., Rasper D.M., Timkey T, Garcia-Calvo M, Houtzager V.M., Nordstrom P.A., Roy S, Vaillancourt J.P., Chapman K.T., Nicholson D.W. (1997) A combinatorial approach defines specificities of members of the caspase family and granzyme B functional relationships established for key mediators of apoptosis. J Biol Chem 272: 17907–17911PubMedCrossRefGoogle Scholar
  29. Wang S, Miura M, Jung Y.K., Zhu H, Gagliardini V, Shi L, Greenberg A.H., Yuan J (1996) Identification and characterization of Ich-3, a member of the interleukin-1β converting enzyme (ICE)/Ced-3 family and an upstream regulator of ICE. J Biol Chem 271:20580–20587PubMedCrossRefGoogle Scholar
  30. Wang S, Miura M, Jung Y-K, Zhu H, Li E, Yuan J (1998) Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell 92: 501–509PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2000

Authors and Affiliations

  • S. Hisahara
    • 1
    • 3
  • R. Takano
    • 1
  • S. Shoji
    • 3
  • H. Okano
    • 1
    • 2
  • M. Miura
    • 1
    • 2
  1. 1.Department of Neuroanatomy, Biomedical Research CenterOsaka University Medical SchoolSuita, OsakaJapan
  2. 2.Core Research for Evolutional Science and Technology (CREST)Japan Science and Technology Corporation (JST)Minato-kuTokyo
  3. 3.Department of NeurologyInstitute of Clinical Medical Sciences, University of TsukubaIbarakiJapan

Personalised recommendations