Skip to main content
SpringerLink
Log in

Cytokines, Signal Transduction, and Inflammatory Demyelination: Review and Hypothesis

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

The mechanism of focal demyelination in multiple sclerosis has been a long-standing enigma of this disorder. Cytokines, a diverse family of signalling molecules, are viewed as potential mediators of the process based on clinical observations and studies with animal models and tissue/cell culture systems. Myelin and oligodendrocyte (OL) destruction occur in cultured preparations subjected to cytokines such as tumor necrosis factor-α (TNFα) and lymphotoxin (LT). Many studies have shown these and other cytokines to be elevated at lesion sites and in the CSF of multiple sclerosis (MS) patients, with similar findings in animal models. Some variability in the nature of MS lesion formation has been reported, both OLs and myelin being primary targets. To account for myelin destruction in the presence of apparently functional OLs we hypothesize that cytokines such as TNFα and LTα contribute to myelin damage through triggering of specific reactions within the myelin sheath. We further propose that neutral sphingomyelinase (SMase) is one such enzyme, two forms of which have been detected in purified myelin. An additional event is accumulation of cholesterol ester, apparently a downstream consequence of cytokine-induced SMase. The resulting lipid changes are viewed as potentially destabilizing to myelin, which may render it more vulnerable to attack by invading and resident phagocytes.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Ruddle, N. H., and Waksman, B. H. 1968. Cytotoxicity mediated by soluble antigen and lymphocytes in delayed hypersensitivity. III. Analysis of mechanism. J. Exp. Med. 128:1267-1269.

    PubMed  Google Scholar 

  2. Meltzer, M. S., and Bartlett, G. C. 1972. Cytotoxicity in vitro by products of specifically stimulated spleen cells: susceptibility of tumor cells and normal cells. J. Natl. Cancer Inst. 49:1439-1443.

    PubMed  Google Scholar 

  3. Vilcek, J., and Lee, T. H. 1991. Tumor necrosis factor: new insights into the molecular mechanisms of its multiple actions. J. Biol. Chem. 266:7313-7316.

    PubMed  Google Scholar 

  4. Tracey, K. C., and Cerami, A. 1993. Tumor necrosis factor, other cytokines and disease. Annu. Rev. Cell Biol. 9:317-343.

    PubMed  Google Scholar 

  5. Jacob, C. O. 1992. Tumor necrosis factor α in autoimmunity: pretty girl or old witch? Immunol. Today 13:122-125.

    PubMed  Google Scholar 

  6. Cheng, B., Christakos, S., and Mattson, M. 1994. Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis. Neuron 12:139-153.

    PubMed  Google Scholar 

  7. Ryffel, B., and Mihatsch, M. J. 1993. TNF receptor distribution in human tissues. Internat. Rev. Experim. Pathol. 34B:149-156.

    Google Scholar 

  8. Gendron, R. L., Nestel, F. P., and Lapp, W. S. 1991. Expression of tumor necrosis factor alpha in the developing nervous system. Int. J. Neurosci. 60:129-136.

    PubMed  Google Scholar 

  9. Merrill, J. E. 1992. Tumor necrosis factor alpha, interleukin 1 and related cytokines in brain development: normal and pathologic. Dev. Neurosci. 14:1-10.

    PubMed  Google Scholar 

  10. Bazzoni, F., and Beutler, B. 1996. The tumor necrosis factor ligand and receptor families. New Engl. J. Med. 334:1717-1725.

    PubMed  Google Scholar 

  11. Benveniste, E. N., and Benos, D. J. 1995. TNF-α-and IFN-γ-mediated signal transduction pathways: effects on glial cell gene expression and function. FASEB J. 9:1577-1584.

    PubMed  Google Scholar 

  12. ffrench-Constant, C. 1994. Pathogenesis of multiple sclerosis. Lancet 343:271-275.

    PubMed  Google Scholar 

  13. Eng, L. F., Ghirnikar, R. S., and Lee, Y. L. 1996. Inflammation in EAE: role of chemokine/cytokine expression by resident and infiltrating cells. Neurochem. Res. 21:511-525.

    PubMed  Google Scholar 

  14. Olsson, T. 1995. Critical influences of the cytokine orchestration on the outcome of myelin antigen-specific T-cell autoimmunity in experimental autoimmune encephalomyelitis and multiple sclerosis. Immunol. Revs. 144:245-268.

    Google Scholar 

  15. Hafler, D. A., and Weiner, H. L. 1995. Immunologic mechanisms and therapy in multiple sclerosis. Immunol. Revs. 144:75-107.

    Google Scholar 

  16. Steinman, L. 1996. Multiple Sclerosis: a coordinationed immunological attack against myelin in the central nervous system. Cell 85:299-302.

    PubMed  Google Scholar 

  17. Merrill, J. E., and Benveniste, E. N. 1996. Cytokines in inflammatory brain lesions: helpful and harmful. Trends Neurosci. 19:331-338.

    PubMed  Google Scholar 

  18. Ransohoff, R. M., and Bo, L. 1996. Cytokines in CNS inflammation: status of experimental autoimmune encephalomyelitis and multiple sclerosis as cytokine-regulated delayed-type hypersensitivity reactions. Pages 221-237, in Ransohoff, R. M., and Benveniste, E. N. (eds.), Cytokines and the CNS. CRC Press, Boca Raton, Florida.

    Google Scholar 

  19. Brosnan, C. F., and Raine, C. S. 1996. Mechanisms of immune injury in multiple sclerosis. Brain Pathol. 6:243-257.

    PubMed  Google Scholar 

  20. Navikas, V., and Link, H. 1996. Review: cytokines and the pathogenesis of multiple sclerosis. J. Neurosci. Res. 45:322-333.

    PubMed  Google Scholar 

  21. Norton, W. T., and Poduslo, S. E. 1973. Myelination in rat brain: method of myelin isolation. J. Neurochem. 21:749-757.

    PubMed  Google Scholar 

  22. Norton, W. T., and Autilio, L. A. 1966. The lipid composition of purified bovine brain myelin. J. Neurochem. 13:213-222.

    PubMed  Google Scholar 

  23. Norton, W. T., and Cammer, W. 1984. Isolation and characterization of myelin. Pages 147-195, in Morell, P. (ed.), Myelin. Plenum Press, New York.

    Google Scholar 

  24. Robbins, D. S., Shirazi, Y., Drysdale, B.-E., Lieberman, A., Shin, H. S., and Shin, M. L. 1987. Production of cytotoxic factor for oligodendrocytes by stimulated astrocytes. J. Immunol. 139:2593-2597.

    PubMed  Google Scholar 

  25. Selmaj, K. W., and Raine, C. S. 1988. Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro. Ann. Neurol. 23:339-346.

    PubMed  Google Scholar 

  26. Brosnan, C. F., Selmaj, K., and Raine, C. S. 1988. Hypothesis: a role for tumor necrosis factor in immune-mediated demyelination and its relevance to multiple sclerosis. J. Neuroimmunol. 18:87-94.

    PubMed  Google Scholar 

  27. Selmaj, K. W., Raine, C. S., Farooq, M., Norton, W. T., and Brosnan, C. F. 1991. Cytokine cytotoxicity against oligodendrocytes: apoptosis induced by lymphotoxin. J. Immunol. 147:1522-1529.

    PubMed  Google Scholar 

  28. Louis, J.-C, Magal, E., Takayama, S., and Varon, S. 1993. CNTF protection of oligodendrocytes against natural and tumor necrosis factor-induced death. Science 259:689-692.

    PubMed  Google Scholar 

  29. McLarnon, J. G., Michikawa, M., and Kim S. U. 1993. Effects of tumor necrosis factor on inward potassium current and cell morphology in cultured human oligodendrocytes. Glia 9:120-126.

    PubMed  Google Scholar 

  30. Soliven, B., and Szuchet, S. 1995. Signal transduction pathways in oligodendrocytes: role of tumor necrosis factor-α. Int. J. Devl. Neurosci. 13:351-367.

    Article  Google Scholar 

  31. Dugandzija-Novakovic, S., and Shrager, P. 1995. Survival, development, and electrical activity of central nervous system myelinated axons exposed to tumor necrosis factor in vitro. J Neurosci. Res. 40:117-126.

    PubMed  Google Scholar 

  32. Agresti, C., D'Urso, D., and Levi, G. 1996. Reversible inhibitory effects of interferon-γ and tumor necrosis factor-α on oligodendroglial lineage cell proliferation and differentiation in vitro. Eur. J. Neurosci. 8:1106-1116.

    PubMed  Google Scholar 

  33. Andrews, T., Zhang, P., and Bhat, N. R. 1996. Cytokines, ceramide and oligodendrocyte cytotoxicity. J. Neurochem. 66(Suppl.):S89B.

    Google Scholar 

  34. Merrill, J. E. 1991. The effects of IL1 and TNF alpha on astrocytes, microglia, oligodendrocytes, and glial precursors in vitro. Dev. Neurosci. 13:130-137.

    PubMed  Google Scholar 

  35. Tchelingerian, J.-L., Monge, M., Le Saux, F., Zalc, B., and Jacque, C. 1995. Differential oligodendroglial expression of tumor necrosis factor receptors in vivo and in vitro. J. Neurochem. 65:2377-2380.

    PubMed  Google Scholar 

  36. Jenkins, H. G., and Ikeda, H. 1992. Tumor necrosis factor causes an increase in axonal transport of protein and demyelination in the mouse optic nerve. J. Neurolog. Sci. 108:99-104.

    Article  Google Scholar 

  37. Butt, A. M., and Jenkins, H. G. 1994. Morphological changes in oligodendrocytes in the intact mouse optic nerve following intravitreal injection of tumor necrosis factor. J. Immunol. 51:27-33.

    Google Scholar 

  38. Simmons, R. D., and Willenborg, D. O. 1990. Direct injection of cytokines into the spinal cord causes autoimmune encephalomyelitis-like inflammation. J. Neurol. Sci. 100:37-42.

    PubMed  Google Scholar 

  39. McLaurin, J., D'Souza, S., Stewart, J., Blain, M., Beaudet, A., Nalbantoglu, J., and Antel, J. P. 1995. Effect of tumor necrosis factor α and β on human oligodendrocytes and neurons in culture. Int. J. Devl. Neurosci. 13:369-381.

    Article  Google Scholar 

  40. D'Souza, S., Alinauskas, K., McCrea, E., Goodyer, C., and Antel, J. P. 1995. Differential susceptibility of human CNS-derived cell populations to TNF-dependent and independent immune-mediated injury. J. Neurosci. 15:7293-7300.

    PubMed  Google Scholar 

  41. Merrill, J. E., and Zimmerman, R. P. 1991. Natural and induced cytoxicity of oligodendrocytes by microglia is inhibitable by TGFβ. Glia 4:327-331.

    PubMed  Google Scholar 

  42. Peck, R., Brockhaus, M., and Frey, J. R. 1989. Cell surface tumor necrosis factor (TNF) accounts for monocyte-and lymphocyte-mediated killing of TNF-resistant target cells. Cell Immunol. 122:1-10.

    PubMed  Google Scholar 

  43. Pennica, D., Nedwin, G. E., Hayflick, J. S., Seeburg, P. H., Derynck, R., Palladino, M. A., Kohn, W. J., Aggarwal, B. B., and Goeddel, D. V. 1984. Human tumor necrosis factor; precursor, structure, expression and homology to lymphotoxin. Nature (London) 312:724-729.

    Article  Google Scholar 

  44. Chung, I. Y., and Benveniste, E. N. 1990. Tumor necrosis factor-α production by astrocytes. 1990. J. Immunol. 144:2999-3007.

    PubMed  Google Scholar 

  45. Selmaj, K. W., Farooq, M., Norton, W. T., Raine, C. S., and Brosnan, C. F. 1990. Proliferation of astrocytes in vitro in response to cytokines. A primary role for tumor necrosis factor. J. Immunol. 144:129-135.

    PubMed  Google Scholar 

  46. Benveniste, E. N., Kwon, J. B., Chung, W. J., Sampson, J., Pandya, K., and Tang, L.-P. 1994. Differential modulation of astrocyte cytokine gene expression by TGFβ. J. Immunol. 153:5210-5221.

    PubMed  Google Scholar 

  47. Benveniste, E. N., Sparacio, S. M., Norris, J. G., Grenett, H. E., and Fuller, G. M. 1990. Induction and regulation of regulation of interleukin-6 gene expression in rat astrocytes. J. Neuroimmunol. 30:201-212.

    PubMed  Google Scholar 

  48. Benveniste, E. N., Tang, L. P., and Law, R. M. 1995. Differential regulation of astrocyte TNF-α expression by the cytokines TGF-β, IL-6, and IL-10. Int. J. Dev. Neurosci. 13:341-349.

    PubMed  Google Scholar 

  49. Hurwitz, A. A., Lyman, W. D., Guida, M. P., Calderon, T. M., and Berman, J. W. 1992. Tumor necrosis factor α induces adhesion molecule expression on human fetal astrocytes. J. Exp. Med. 176:1631-1636.

    PubMed  Google Scholar 

  50. Shrikant, P., Chung, I. Y., Ballestas, M., and Benveniste, E. N. 1944. Regulation of intercellular adhesion molecule-1 gene expression by tumor necrosis factor-α, interleukin-1β. and interferon-γ in astrocytes. J. Neuroimmunol. 51:209-220.

    Article  Google Scholar 

  51. Eddleston, M., and Mucke, L. 1993. Molecular profile of reactive astrocytes. Implication for their role in neurological disease. Neurosci. 54:15-36.

    Article  Google Scholar 

  52. Chung, I. Y., Norris, J. G., and Benveniste, E. N. 1991. Differential tumor necrosis factor α expression by astrocytes from experimental allergic encephalomyelitis-susceptible and-resistant rat strains. J. Exp. Med. 173:801-811.

    PubMed  Google Scholar 

  53. Gehrmann, J., Matsumoto, Y., and Kreutzberg, G. W. 1995. Microglia: intrinsic immunoeffector cell of the brain. Brain Res. Rev. 20:269-287.

    PubMed  Google Scholar 

  54. Kreutzberg, G. W. 1996. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19:312-318.

    PubMed  Google Scholar 

  55. Merrill, J. E., Ignarro, L. J., Sherman, M. P., Melinek, J., and Lane T. E. 1993. Microglial cell cytoxicity of oligodendrocytes is mediated through nitric oxide. J. Immunol. 151:2132-2141.

    PubMed  Google Scholar 

  56. Hofman, F. M., Hinton, D. R., Johnson, K., and Merrill, J. E. 1989. Tumor necrosis factor identified in multiple sclerosis brain. J. Exp. Med. 170:607-612.

    PubMed  Google Scholar 

  57. Selmaj, K., Raine, C. S., Cannella, B., Brosnan, C. F. 1991. Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions. J. Clin Invest. 87:949-954.

    PubMed  Google Scholar 

  58. Cannella, B., and Raine, C. S. 1995. The adhesion molecule and cytokine profile of multiple sclerosis lesions. Ann. Neurol. 37:424-435.

    PubMed  Google Scholar 

  59. Wucherpfennig, K. W., Newcombe, J. L. H., Keddy, C., Cuzner, M. L., and Hafler, D. A. 1992. T cell receptor Vα-Vβ repertoire and cytokine gene expression in active multiple sclerosis lesions. J. Exp. Med. 175:993-1002.

    PubMed  Google Scholar 

  60. Hofman, F. M., von Hahnwehr, R. I., Dinarello, C. A., Mizel, S. B., Hinton, D., and Merrill, J. E. 1986. Immunoregulatory molecules and IL2 receptors identified in multiple sclerosis lesions. J. Immunol. 136:3239-3245.

    PubMed  Google Scholar 

  61. Traugott, U., and Lebon, P. 1988. Multiple sclerosis: involvement of interferons in lesion pathogenesis. Ann. Neurol. 24:243-251.

    PubMed  Google Scholar 

  62. Woodroofe, M. N., and Cuzner, M. L. 1993. Cytokine mRNA expression in inflammatory multiple sclerosis lesions: detection by non-radioactive in situ hybridization. Cytokine 5:583-588.

    PubMed  Google Scholar 

  63. Sharief, M. K., and Hentges, R. 1991. Association between tumor necrosis-alpha and disease progression in patients with multiple sclerosis. N. Engl. J. Med. 325:467-472.

    PubMed  Google Scholar 

  64. Beck, J., Rondot, P., Catinot, L. I., Falcoff, E., Kirchner, H., and Wietzerbin, J. 1988. Increased production of interferon gamma and tumor necrosis factor precedes clinical manifestation in MS: do cytokines trigger off exacerbations? Acta Neurol. Scand. 78:318-323.

    PubMed  Google Scholar 

  65. Franciotta, D. M., Grimaldi, L. M., Martino, G. V., Piccolo, G., Bergamaschi, R., Citterio, A., and Melzi d'Eril, G. V. 1989. Tumor necrosis factor in serum and cerebrospinal fluid from patients with multiple sclerosis. Ann. Neurol. 26:767-789.

    Google Scholar 

  66. Hauser, S. L., Doolittle, T. H., Lincoln, R., Brown, R. H., and Dinarello, C. A. 1990. Cytokine accumulations in CSF of multiple sclerosis patients: frequent detection of interleukin-1 and tumor necrosis factor but not interleukin-6. Neurol. 40:1735-1739.

    Google Scholar 

  67. Sharief, M. K., and Thompson, E. J. 1992. In vivo relationship of tumor necrosis factor-α to blood-brain barrier damage in patients with active multiple sclerosis. J. Neurimmunol. 38:27-34.

    Article  Google Scholar 

  68. Olsson, T., Wang, W. Z., Hojeberg, B., Kostulas, V., Jiang, Y. P., Andersson, G., Ekre, H. P., and Link, H. 1990. Autoreactive T lymphocytes in multiple sclerosis determined by antigen induced secretion of interferon-gamma. J. Clin. Invest. 86:981-985.

    PubMed  Google Scholar 

  69. Link, J, Soderstrom, M., Olsson, T., Hojeberg, B., Ljungdahl, A., Gustafsson, A., and Link, H. 1994. Increased TGF-β, IL-4 and IFN-γ in multiple sclerosis. Ann. Neurol. 36:379-386.

    PubMed  Google Scholar 

  70. Rieckmann, P., Albrecht, M., Kitze, B., Weber, T., Tumani, H., Broocks, A., and Luer, P. S. 1994. Cytokine mRNA levels in mononuclear blood cells from patients with multiple sclerosis. Neurol. 44:1523-1526.

    Google Scholar 

  71. Navikas, V., He, B., Link, J., Haglund, M., Soderstrom, M., Fredrickson, S., Ljungdahl, A., Hojeberg, B., Qiao, J., Olsson, T., and Link, H. 1996. Augmented expression of tumor necrosis factor-α and lymphotoxin in mononuclear cells in multiple sclerosis and optic neuritis. Brain 119:213-223.

    PubMed  Google Scholar 

  72. Rieckmann, P., Albrecht, M., Kitze, B., Weber, T., Tumani, H., Brooks, A., Luer, W., Helwig, A., and Poser, S. 1995. TNF-α mRNA expression in patients with relapsing-remitting multiple sclerosis is associated with disease activity. Ann. Neurol. 37:82-88.

    PubMed  Google Scholar 

  73. Zipp, F., Weber, F., Huber, S., Sotgiu, S., Czlonkowska, A., Holler, E., Albert, E., Weiss, E. H., Wekerle, H., and Hohlfeld, R. 1995. Genetic control of multiple sclerosis: increased production of lymphotoxin and tumor necrosis factor-α by HLA-DR2+ T cells. Ann. Neurol. 38:723-730.

    PubMed  Google Scholar 

  74. Gallo, P., Piccino, M. G., Krzalic, L., and Tavolato, B. 1989. Tumor necrosis factor alpha (TNFα) and neurological diseases: failure in detecting TNFα in the cerebrospinal fluid from patients with multiple sclerosis, AIDS dementia complex, and brain tumors. J. Neuroimmunol. 23:41-44.

    PubMed  Google Scholar 

  75. Peter, J. B., Boctor, F. N., and Tourtellotte, W. W. 1991. Serum and CSF levels of IL-2, sIL-2R, TNF-alpha, and IL-1 beta in chronic progressive multiple sclerosis: expected lack of clinical utility. Neurol. 41:121-123.

    Google Scholar 

  76. Tsukada, N., Miyagi, K., Matsuda, M., Yanagisawa, N., and Yone, K. 1991. Tumor necrosis factor and interleukin-1 in the CSF and sera of patients with multiple sclerosis. J. Neurol. Sci. 102:230-234.

    Article  Google Scholar 

  77. Trotter, J. L., Collins, K. G., and Van Der Veen, R. C. 1991. Serum and cytokine levels in chronic progressive multiple sclerosis: interleukin-2 levels parallel tumor necrosis factor levels. J. Neuroimmunol. 33:29-36.

    PubMed  Google Scholar 

  78. Maimone, D., Gregory, S., Arnason, B. G., and Reder, A. T. 1991. Cytokine levels in the cerebrospinal fluid and serum of patients with multiple sclerosis. J. Neuroimmunol. 32:67-74.

    PubMed  Google Scholar 

  79. Lassmann, H., and Vass, K. 1995. Are current immunological concepts of multiple sclerosis reflected by the immunopathology of its lesions? Springer Semin. Immunopathol. 17:77-87.

    PubMed  Google Scholar 

  80. Lisak, R. P. 1986. Interferon and multiple sclerosis. Ann. Neurol. 20:273.

    Google Scholar 

  81. Olsson, T. 1995. Critical Influences of the cytokine orchestration on the outcome of myelin antigen-specific T-cell autoimmunity in experimental autoimmune encephalomyelitis and multiple sclerosis. Immunol. Revs. 133:245-268.

    Google Scholar 

  82. Sun, J. B., Olsson, T., Wang, W. Z., Xiao, B. G., Kostulas, V., Frederikson, S., Ekre, H. P., and Link, H. 1991. Autoreactive T and B cells responding to myelin proteolipid protein in multiple sclerosis and controls. Eur. J. Immunol. 21:1461-1468.

    PubMed  Google Scholar 

  83. Sun, J. B., Link, H., Olsson, T., Xiao, B. G., Andersson, G., Ekre, H. P., Linington, C., and Diener, P. 1991. T and B cell responses to myelin-oligodendrocyte glycoprotein in multiple sclerosis. J. Immunol. 146:1490-1495.

    PubMed  Google Scholar 

  84. Panitch, H. S., Hirsch, R. L., Schindler, J., and Johnson, K. P. 1987. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurol. 37:1097-1102.

    Google Scholar 

  85. Paty, D. W., Li, D. K. B., the UBC MS/MRI study group, and the IFNB Multiple Sclerosis Study group. 1993. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis: MRI results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurol. 43:662-667.

    Google Scholar 

  86. The IFNB Multiple Sclerosis Study Group. 1993. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis: clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 43:655-661.

    Google Scholar 

  87. Panitch, H. S., and Bever, C. T. Jr. 1993. Clinical trials of interferons in multiple sclerosis. What have we learned? J. Neuroimmunol. 46:155-164.

    PubMed  Google Scholar 

  88. Brod, S. A., Marshall, G. D. Jr., Henninger, E. M., Sriram, S., Khan, M., and Wolinsky, J. S. 1996. Interferon-β1b treatment decreases tumor necrosis factor-α and increases interleukin-6 production in multiple sclerosis. Neurology 46:1633-1638.

    PubMed  Google Scholar 

  89. Goldberg, M., Belkowski, L. S., and Bloom, B. R. 1990. Regulation of macrophage function by interferon-γ. Somatic cell genetic approaches in murine macrophage cell lines to mechanisms of growth inhibition, the oxidative burst, and expression of the chronic granulomatous disease gene. J. Clin. Invest. 85:563-569.

    PubMed  Google Scholar 

  90. Collart, M. A., Belin, D., Vassalli, J. D., de Kossodo, S., and Vassalli, P. 1986. Gamma-interferon enhances macrophage transcription of the tumor necrosis factor/cachectin, interleukin-1 and urokinase genes, which are controlled by short-lived repressors. J. Exp. Med. 164:2113-2118.

    PubMed  Google Scholar 

  91. Skoskiewicz, M. J., Calvin, R. B., Schneeberger, E. E., and Russel, P. S. 1985. Widespread and selective induction of major histocompatibility complex determined antigens in vivo by gamma-interferon. J. Exp. Med. 162:1645-1664.

    PubMed  Google Scholar 

  92. May, M. J. and Ager, A. 1992. ICAM-1-independent lymphocyte transmigration across high endothelium: differential up-regulation by interferon γ, tumor necrosis factor-α and interleukin 1β. Eur. J. Immunol. 22:219-226.

    PubMed  Google Scholar 

  93. Barten, D. M., and Ruddle, N. H. 1994. Vascular cell adhesion molecule-1 modulation by tumor necrosis factor in experimental allergic encephalomyelitis. J. Neuroimmunol. 51:123-133.

    PubMed  Google Scholar 

  94. Krakowski, M., and Owens, T. 1996. Interferon-γ confers resistance to experimental allergic encephalomyelitis. Eur. J. Immunol. 26:1641-1646.

    PubMed  Google Scholar 

  95. Villarroyo, H., Violleau, K., Younes-Chennoufi, A. B., Baumann, N. 1996. Myelin-induced experimental allergic encephalomyelitis in Lewis rats: tumor necrosis factor α levels in serum and cerebrospinal fluid. Immunohistochemical expression in glial cells and macrophages of optic nerve and spinal cord. J. Neuroimmunol. 64:55-61.

    PubMed  Google Scholar 

  96. Powell, M., Mitchell, D., Lederman, J., Buckmeier, J., Zamvil, S. S., Graham, M., Ruddle, N. H., and Steinman, L. 1990. Lymphotoxin and tumor necrosis factor-alpha production by myelin basic protein-specific T cell clones correlates with encephalogeniticity. Int. Immunol. 2:539-544.

    PubMed  Google Scholar 

  97. Merrill, J. E., Kono, D. H., Clayton, J., Ando, D. G., and Hinton, D. R. 1992. Inflammatory leukocytes and cytokines in the peptide-induced disease of experimental allergic encephalomyelitis in SJL and B10.PL mice. Proc. Natl. Acad. Sci. USA 89:574-578.

    Google Scholar 

  98. Raine, C. S., Traugott, U., Farooq, M., Bornstein, M. B., and Norton, W. T. 1981. Augmentation of immune-mediated demyelination by lipid haptens. Lab. Invest. 45:174-182.

    PubMed  Google Scholar 

  99. Pender, M. P. 1988. The pathophysiology of myelin basic protein-induced acute experimental allergic encephalomyelitis in the Lewis rat. J. Neurol. Sci. 86:277-289.

    PubMed  Google Scholar 

  100. Kennedy, M. K., Torrance, D. S., Picha, K. S., and Mohler, K. M. 1992. Analysis of cytokine mRNA expression in the central nervous system of mice with experimental autoimmune encephalomyelitis reveals that IL-10 mRNA expression correlates with recovery. J. Immunol. 149:2496-2505.

    PubMed  Google Scholar 

  101. Baker, D., O'Neill, J. K., and Turk, J. L. 1991. Cytokines in the central nervous system of mice during chronic relapsing experimental allergic encephalomyelitis. Cell Immunol. 134:505-510.

    PubMed  Google Scholar 

  102. Weinberg, A. D., Wyrick, G., Celnick, B., Vainiene, M., Bakke, A., Offner, H., and Vandenbark, A. A. 1993. Lymphokine mRNA expression in the spinal cords of Lewis rats with experimental autoimmune encephalomyelitis is associated with host recruited CD45R hi/CD4+ population during recovery. J. Neuroimmunol. 48:105-118.

    PubMed  Google Scholar 

  103. Renno, T., Lin, J.-Y., Piccirillo, C., Antel, J., Owens, T. 1994. Cytokine production by cells in cerebrospinal fluid during experimental allergic encephalomyelitis in SJL/J mice. J. Neuroimmunol. 49:1-7.

    PubMed  Google Scholar 

  104. Issazadeh, S., Mustafa, M., Ljungdahl, A., Hojeberg, B., Dagerling, A., Elde, R., and Olsson, T. 1995. Interferon γ, interleukin 4, and transforming growth factor β in experimental autoimmune encephalomyelitis in Lewis rats: dynamics of cellular mRNA expression in the central nervous system and lymphoid cells. J. Neurosci. Res. 40:579-590.

    PubMed  Google Scholar 

  105. Racke, M. K., Burnett, D., Pak, S-H, Albert, P. S., Cannella, B., Raine, C. S., McFarlin, D. E., and Scott, D. E. 1995. Retinoid treatment of experimental allergic encephalomyelitis: IL-4 production correlates with improved disease course. J. Immunol. 154:450-458.

    PubMed  Google Scholar 

  106. Godiska, R., Chantry, D., Dietsch, G. N., and Gray, P. W. 1995. Chemokine expression in murine experimental allergic encephalomyelitis. J. Neuroimmunol. 58:167-176.

    PubMed  Google Scholar 

  107. Ruddle, N. H., Bergman, C. M., McGrath, K. M., Lingenheld, E. G., Grunnet, M. L., Padula, S. J., and Clark, R. B. 1990. An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis. J. Exp. Med. 172:1193-1200.

    PubMed  Google Scholar 

  108. Selmaj, K., Raine, C. S., and Cross, A. H. 1991. Anti-tumor necrosis factor therapy abrogates autoimmune demyelination. Ann. Neurol. 30:694-700.

    PubMed  Google Scholar 

  109. Selmaj, K., Papierz, W., Glabinski, A., and Kohno, T. 1995. Prevention of chronic relapsing experimental autoimmune encephalomyelitis by soluble tumor necrosis factor receptor. J. Neuroimmunol. 56:135-141.

    PubMed  Google Scholar 

  110. Martin, D., Near, S. L., Bendele, A., and Russell, D. A. 1995. Inhibition of tumor necrosis factor is protective against neurologic dysfunction after active immunization of Lewis rats with myelin basic protein. Experim. Neurol. 131:221-228.

    Article  Google Scholar 

  111. Issazadeh, S., Lorentzen, J. C., Mustafa, M. I., Hojeberg, B., Mussener, A., and Olsson, T. 1996. Cytokines in relapsing experimental autoimmune encephalomyelitis in DA rats: persistent mRNA expression of proinflammatory cytokines and absent expression of interleukin-10 and transforming growth factor-β. J. Neuroimmunol. 69:103-115.

    PubMed  Google Scholar 

  112. Probert, L., Akassoglou, K., Pasparakis, M., Kontogeorgos, G., and Kollias, G. 1995. Spontaneous inflammatory demyelinating disease in transgenic mice showing central nervous system-specific expression of tumor necrosis factor α. Proc. Natl. Acad. Sci. (USA) 92:11294-8.

    Google Scholar 

  113. Billiau, A., Heremans, H., Vandekerckhove, F., Dijkmans, R., Sobis, H., Meulepas, E., and Carton, H. 1988. Enhancement of experimental autoimmune encephalomyelitis in mice by antibodies against IFN-γ. J. Immunol. 140:1506-1510.

    PubMed  Google Scholar 

  114. Duong, T. T., Finkelman, F. D., Singh, B., and Strejan, G. H. 1994. Effect of anti-interferon-gamma monoclonal antibody treatment on the development of experimental autoimmune encephalomyelitis in resistant mouse strains. J. Neuroimmunol. 53:101-107.

    PubMed  Google Scholar 

  115. Duong, T. T., St. Louis, J., Gilbert, J. J., Finkelman, F. D., and Strejan, G. H. 1992. Effect of anti-interferon-gamma and anti-interleukin-2 monoclonal antibody treatment on the development of actively and passively induced experimental autoimmune encephalomyelitis in the SJL/J mouse. J. Neuroimmunol. 36:105-115.

    PubMed  Google Scholar 

  116. Mustafa, M. I., Diener, P., Hojeberg, B., Van der Meide, P., and Olsson, T. 1991. T cell immunity and inteferon-gamma secretion during experimental autoimmune encephalomyelitis in Lewis rats. J. Neuroimmunol. 31:165-177.

    PubMed  Google Scholar 

  117. Linington, C., Bradl, M., Lassman, H., Brunner, Ch., and Vass, K. 1988. Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies against myelin/oligodendroglia glycorprotein. Am. J. Pathol. 130:443-454.

    PubMed  Google Scholar 

  118. Raine, C. S., Johnson, A. B., Marcus, D., Suzuki, A., and Bornstein, M. B. 1981. Demyelination in vitro. Adsorption studies demonstrate that galactocerebroside is a major target. J. Neurol. Sci. 52:117-131.

    PubMed  Google Scholar 

  119. Raine, C. S. 1984. Biology of disease. The analysis of autoimmune demyelination: its impact on multiple sclerosis. Lab. Invest. 50:608-635.

    PubMed  Google Scholar 

  120. Brosnan, C. F., Traugott, U., and Raine, C. S. 1983. Analysis of humoral and cellular events and the role of lipid haptens during CNS demyelination. Acta Neuropathol. Suppl. 9:59-70.

    Google Scholar 

  121. Prineas, J. W. 1985. The neuropathology of multiple sclerosis. Handb. Clin. Neurol. 47:213-257.

    Google Scholar 

  122. Trotter, J., DeJong, L. J., and Smith, M. E. 1986. Opsinization with antimyelin antibody increases the uptake and intracellular metabolism of myelin in inflammatory macrophages. J. Neurochem. 47:779-789.

    PubMed  Google Scholar 

  123. Sommer, M. A., Forno, L. S., and Smith, M. E. 1992. EAE cerebrospinal fluid augments in vitro phagocytosis and metabolism of CNS myelin by macrophages. J. Neurosci. Res. 32:384-394.

    PubMed  Google Scholar 

  124. Glynn, P., and Linington, C. 1989. Cellular and molecular mechanisms of autoimmune demyelination in the central nervous system. CRC Critical Rev. Neurobiol. 4:367-385.

    Google Scholar 

  125. Silverman, B. A., Carney, D. F., Johnson, C. A., Vanguri, P., and Shin, M. L. 1984. Isolation of membrane attack complex of complement from myelin membranes treated with serum complement. J. Neurochem. 42:1024-1030.

    PubMed  Google Scholar 

  126. Johnson, H. M., Torres, B. A., and Soos, J. M. 1996. Superantigens: structure and relevance to human disease. Proc. Soc. Exp. Biol. Med. 212:99-109.

    PubMed  Google Scholar 

  127. Rodriguez, M., Scheithauer, B. W., Forbes, G., Kelly, P. J. 1993. Oligodendrocyte injury is an early event in lesions of multiple sclerosis. Mayo Clin. Proc. 68:627-636.

    PubMed  Google Scholar 

  128. Raine, C. S., Scheinberg, L., and Waltz, J. M. 1981. Multiple sclerosis: oligodendrocyte survival and proliferation in an active established lesion. Lab. Invest. 45:534-546.

    PubMed  Google Scholar 

  129. Prineas, J. W., Kwoon, E. E., Goldenberg, P. Z., Ilyas, A. A., Quarles, R. H., Benjamins, J. A., and Sprinkle, T. J. 1989. Multiple sclerosis. Oligodendrocyte proliferation and differentiation in fresh lesions. Lab. Invest. 61:489-503.

    PubMed  Google Scholar 

  130. Prineas, J. W., Bernard, R. O., Kwon, E. E., Sharer, L. R., and Cho, E. S. 1993. Multiple sclerosis: remyelination of nascent lesions. Ann Neurol. 33:137-151.

    PubMed  Google Scholar 

  131. Prineas, J. W., Barnard, R. O., Revesz, T., Kwon, E. E., Sharer, L., and Cho E. S. 1993. Multiple Sclerosis. Pathology of recurrent lesions. Brain 116:681-693.

    PubMed  Google Scholar 

  132. Brück, W., Schmied, M., Suchanek, G., Brück, Y., Breitschopf, H., Poser, S., Piddlesden, S., and Lassmann, H. 1994. Oligodendrocytes in the early course of MS. Ann. Neurol. 35:65-73.

    PubMed  Google Scholar 

  133. Ozawa, K., Suchanek, G., Breitschopf, H., Bruck, W., Budka, H., Jellinger, K., and Lassmann, H. 1994. Patterns of oligodendroglia pathology in multiple sclerosis. Brain 117:1311-1322.

    PubMed  Google Scholar 

  134. Rosen, J. L., Brown, M. J., Hickey, W. F., and Rostami, A. 1990. Early myelin lesions in experimental allergic neuritis. Muscle and Nerve 13:629-636.

    PubMed  Google Scholar 

  135. Chakraborty, G., Ziemba, S., and Ledeen, R. W. 1995. Signal transduction induced by TNF-α promotes cholesterol ester formation in mouse brain. J. Neurochem. 64(Suppl.): S61B.

    Google Scholar 

  136. Chakraborty, G., Ziemba, S., Drivas, A., and Ledeen, R. W. 1997. Myelin contains neutral sphingomyelinase activity that is stimulated by tumor necrosis factor-α. In Press.

  137. Ziemba, S., Chakraborty, G., and Ledeen, R. 1996. Evidence for the presence of Mg2+-dependent neutral sphingomyelinase in CNS myelin. J. Neurochem. 66(Suppl.) S546C.

    Google Scholar 

  138. Yamaguchi, S., and Suzuki, K. 1978. A novel magnesium-independent neutral sphingomyelinase associated with rat central nervous system myelin. J. Biol Chem. 253:4090-4092.

    PubMed  Google Scholar 

  139. Yamanaka, T., Hanada, E., and Suzuki, K. 1981. Acid sphingomyelinase in human brain; improved purification procedures and characterization. J. Biol. Chem. 256:3884-3889.

    PubMed  Google Scholar 

  140. Chatterjee, S. 1994. Neutral sphingomyelinase action stimulates signal transduction of tumor necrosis factor-α in the synthesis of cholesteryl esters in human fibroblasts. J. Biol. Chem. 269:879-882.

    PubMed  Google Scholar 

  141. Hannun, Y. A., and Obeid, L. M. 1995. Ceramide: an intracellular signal for apoptosis. Trends Biochem. Sci. 20:73-77.

    PubMed  Google Scholar 

  142. Kolesnick, R. 1992. Ceramide: a novel second messenger. Trends in Cell Biol. 2:232-236.

    Article  Google Scholar 

  143. Kinouchi, K., Brown, G., Pasternak, G., and Donner, D. 1991. Identification and characterization of receptors for tumor necrosis factor-alpha in the brain. Biochem. Biophys. Res. Commun. 181:1532-1538.

    PubMed  Google Scholar 

  144. Ledeen, R. W. 1992. Enzymes and receptors of myelin. Pages 531-570, in Martenson, R. E. (ed), Myelin Biology and Chemistry. CRC Press, Boca Raton, Florida.

    Google Scholar 

  145. Larocca, J. N., Ledeen, R. W., Dvorkin, B., and Makman, M. H. 1987. Muscarinic receptor binding and muscarinic receptor-mediated inhibition of adenylate cyclase in rat brain myelin. J. Neurosci. 7:3869-3876.

    PubMed  Google Scholar 

  146. Larocca, J. N., Cervone, A., and Ledeen, R. 1987. Stimulation of phosphoinositide hydrolysis in myelin by muscarinic agonist and potassium. Brain Res. 436:357-362.

    PubMed  Google Scholar 

  147. Kahn, D. W., and Morell, P. 1988. Phosphatidic acid and phosphoinositide turnover in myelin and its stimulation by acetylcholine. J. Neurochem. 50:1542-1550.

    PubMed  Google Scholar 

  148. Day, N. S., Berti-Mattera, L. N., and Eichberg, J. 1991. Muscarinic cholinergic receptor-mediated phosphoinositide metabolism in peripheral nerve. J. Neurochem. 56:1905-1913.

    PubMed  Google Scholar 

  149. Iacobelli, S. 1969. The biosynthesis of triphosphoinositide by purified myelin of peripheral nerve. J. Neurochem. 16:909-911.

    PubMed  Google Scholar 

  150. Deshmukh, D. S., Kuizon, S., Bear, W. D., and Brockerhoff, H. 1981. Rapid incorporation in vivo of intracerebrally injected 32Pi into polyphosphoinositides of three subfractions of rat brain myelin. J. Neurochem. 36:594-601.

    PubMed  Google Scholar 

  151. Deshmukh, D. S., Kuizon, S., Bear, W. D., and Brockerhoff, H. 1982. Polyphosphoinositide mono-and diphosphoesterases of three subfractions of rat brain myelin. Neurochem. Res. 7:617-626.

    PubMed  Google Scholar 

  152. Deshmukh, D. S., Bear, W. D., and Brockerhoff, H. 1978. Polyphosphoinositide biosynthesis in three subfractions of rat brain myelin. J. Neurochem. 30:1191-1193.

    PubMed  Google Scholar 

  153. Shaikh, N. A., and Palmer, F. B. St. C. 1976. Deposition of lipids in the developing central and peripheral nervous systems of the chicken. J. Neurochem. 26:597-603.

    PubMed  Google Scholar 

  154. Saltiel, A. R., Fox, J. A., Sherline, P., Sahyoun, N., and Cuatrecasas, P. 1987. Purification of phosphatidylinositol kinase from bovine brain myelin. Biochem. J. 241:759-763.

    PubMed  Google Scholar 

  155. Johnson, E. M., Maeno, H., and Greengard, P. 1971. Phosphorylation of endogenous proteins of rat brain by cyclic adenosine 3′,5′-monophosphate-dependent protein kinase. J. Biol. Chem. 246:7731-7739.

    PubMed  Google Scholar 

  156. Carnegie, P. R., Dunkley, P. R., Kemp, B. E., and Murray, A. W. 1974. Phosphorylation of selected serine and threonine residues in myelin basic protein by endogenous and exogenous protein kinases. Nature (London) 249:147-150.

    Google Scholar 

  157. Miyamoto, E., and Kakiuchi, S. 1974. In vitro and in vivo phosphorylation of myelin basic protein by exogenous and endogenous adenosine 3′,5′-monophosphate-protein kinases in brain. J. Biol. Chem. 249:2769-2777.

    PubMed  Google Scholar 

  158. Wu, N.-C., and Ahmad, F. 1984. Calcium-and cyclic AMP-regulated protein kinases of bovine central nervous system myelin. Biochem. J. 218:923-932.

    PubMed  Google Scholar 

  159. Chakraborty, G., and Ledeen, R. W. 1993. Guanylyl cyclase activity in rat brain myelin and white matter. J. Neurochem. 61:1953-1956.

    PubMed  Google Scholar 

  160. Grabow, M., Chakraborty, G., and Ledeen, R. W. 1996. Characterization of guanylyl cyclase in purified myelin. Neurochem. Res. 21:457-462.

    PubMed  Google Scholar 

  161. Larocca, J. N., Golly, F., and Ledeen, R. W. 1991. Detection of G-proteins in purified bovine brain myelin. J. Neurochem. 57:30-38.

    PubMed  Google Scholar 

  162. Braun, P. E., Horvath, E., Young, V. W., and Bernier, L. 1990. Identification of GTP-binding proteins in myelin and oligodendrocyte membranes. J. Neurosci. Res. 26:16-23.

    PubMed  Google Scholar 

  163. Berti-Mattera, L. N., Douglas, J. G., Mattera, R., and Goraya, T. Y. 1992. Identification of G protein subtypes in peripheral nerve and cultured Schwann cells. J. Neurochem. 59:1729-1735.

    PubMed  Google Scholar 

  164. DesJardins, K. C., and Morell, P. 1983. Phosphate groups modifying myelin basic proteins are metabolically labile; methyl groups are stable. J. Cell Biol. 97:438-446.

    PubMed  Google Scholar 

  165. Gitlin, G., and Singer, M. 1974. Myelin movements in mature mammalian peripheral nerve fibers. J. Morphol. 143:167-176.

    PubMed  Google Scholar 

  166. Mugnaini, E., Osen, K. K., Schnapp, B., and Friedrich, Jr., V. L. 1977. Distribution of Schwann cell cytoplasm and plasmalemmal vesicles (caveolae) in peripheral myelin sheaths. An electron microscopic study with thin sections and freeze-fracturing. J. Neurocytol. 6:647-668.

    PubMed  Google Scholar 

  167. Vos, J. P., Giudici, M. L., van der Bijl, P., Magni, P., Marchesini, S., van Golde, L. M. G., and Lopes-Cardozo, M. 1995. Sphingomyelin is synthesized at the plasma membrane of oligodendrocytes and by purified myelin membranes: a study with fluorescent-and radio-labeled ceramide analogues. FEBS Letts. 368:393-396.

    Article  Google Scholar 

  168. Choi, M. U., and Suzuki, K. 1978. A cholesterol-esterifying enzyme in rat central nervous system myelin. J. Neurochem. 31:879-885.

    PubMed  Google Scholar 

  169. Eto, Y., and Suzuki, K. 1973. Cholesterol ester metabolism in rat brain. J. Biol. Chem. 248:1986-1991.

    PubMed  Google Scholar 

  170. Eto, Y., and Suzuki, K. 1973. Developmental changes of cholesterol ester hydrolases localized in myelin and microsomes of rat brain. J. Neurochem. 20:1475-1477.

    PubMed  Google Scholar 

  171. Eto, Y., and Suzuki. K. 1972. Cholesterol esters in developing rat brain: concentration and fatty acid composition. J. Neurochem. 19:109-115.

    PubMed  Google Scholar 

  172. Li, H., Newcombe, J., Groome, N. P., and Cuzner, M. L. 1993. Characterization and distribution of phagocytic macrophages in multiple sclerosis plaques. Neuropathol. Appl. Neurobiol. 19:214-223.

    PubMed  Google Scholar 

  173. Jagannatha, H. M., and Sastry, P. S. 1981. Ethanolamine plasmalogen and cholesterol ester metabolism in experimental allergic encephalomyelitis. Ind. J. Biochem. Biophys. 18:411-416.

    Google Scholar 

  174. Gordon, H. M., Kucera, G., Salvo, R., and Boss, J. 1992. Tumor necrosis factor induces genes involved in inflammation, cellular and tissue repair, and metabolism in murine fibroblasts. J. Immunol. 148:4021-4027.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurosciences, New Jersey Medical School, UMDNJ 185 South Orange Ave., Newark, NJ, 07103

    Robert W. Ledeen & Goutam Chakraborty

Authors
  1. Robert W. Ledeen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Goutam Chakraborty
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ledeen, R.W., Chakraborty, G. Cytokines, Signal Transduction, and Inflammatory Demyelination: Review and Hypothesis. Neurochem Res 23, 277–289 (1998). https://doi.org/10.1023/A:1022493013904

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1022493013904

Search

Navigation