Skip to main content

PMC Search Update

PMC Beta search will replace the current PMC search the week of September 7, 2025. Try out PMC Beta search now and give us your feedback. Learn more

NCBI home page
Molecular Medicine logoLink to Molecular Medicine
. 1995 Nov;1(7):732–743.

Interferon-gamma-induced oligodendrocyte cell death: implications for the pathogenesis of multiple sclerosis.

T Vartanian 1, Y Li 1, M Zhao 1, K Stefansson 1
PMCID: PMC2230017  PMID: 8612196

Abstract

BACKGROUND: The histopathology of multiple sclerosis (MS) is characterized by a loss of myelin and oligodendrocytes, relative preservation of axons, and a modest inflammatory response. The reasons for this selective oligodendrocyte death and demyelination are unknown. MATERIALS AND METHODS: In light of the T lymphocyte and macrophage infiltrates in MS lesions and the numerous cytokines these cells secrete, the direct influence of cytokines on survival of cultured oligodendrocytes and sensory neurons was investigated. Expression of cytokines in vivo was determined by immunolabeling cryostat sections of snap-frozen tissue containing chronic active lesions from four different patients. The samples were also analyzed for the presence of apoptotic nuclei by in situ labeling of 3'-OH ends of degraded nuclear DNA. RESULTS: The results showed: (i) interferon-gamma (IFN gamma) to be a potent inducer of apoptosis among oligodendrocytes in vitro and that this effect can be reversed by leukemia inhibitory factor (LIF); (ii) IFN gamma has a minimal effect on the survival of cultured neurons; (iii) IFN gamma at the margins of active MS plaques but not in unaffected white matter; (iv) evidence for apoptosis of oligodendrocytes at the advancing margins of chronic active MS plaques. CONCLUSIONS: Injury to a substantial number of oligodendrocytes in MS is the results of programmed cell death rather than necrotic cell death mechanisms. We postulate that IFN gamma plays a role in the pathogenesis of MS by activating apoptosis in oligodendrocytes.

Full text

PDF
732

Images in this article

736FIG. 1
on p.736
737FIG. 2
on p.737
738FIG. 3
on p.738
739FIG. 5
on p.739
740FIG. 6
on p.740

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arends M. J., Morris R. G., Wyllie A. H. Apoptosis. The role of the endonuclease. Am J Pathol. 1990 Mar;136(3):593–608. [PMC free article] [PubMed] [Google Scholar]
  2. Arenzana-Seisdedos F., Virelizier J. L. Interferons as macrophage-activating factors. II. Enhanced secretion of interleukin 1 by lipopolysaccharide-stimulated human monocytes. Eur J Immunol. 1983 Jun;13(6):437–440. doi: 10.1002/eji.1830130602. [DOI] [PubMed] [Google Scholar]
  3. Arnason B. G. Interferon beta in multiple sclerosis. Neurology. 1993 Apr;43(4):641–643. doi: 10.1212/wnl.43.4.641. [DOI] [PubMed] [Google Scholar]
  4. Banati R. B., Gehrmann J., Schubert P., Kreutzberg G. W. Cytotoxicity of microglia. Glia. 1993 Jan;7(1):111–118. doi: 10.1002/glia.440070117. [DOI] [PubMed] [Google Scholar]
  5. Barres B. A., Hart I. K., Coles H. S., Burne J. F., Voyvodic J. T., Richardson W. D., Raff M. C. Cell death and control of cell survival in the oligodendrocyte lineage. Cell. 1992 Jul 10;70(1):31–46. doi: 10.1016/0092-8674(92)90531-g. [DOI] [PubMed] [Google Scholar]
  6. Barres B. A., Schmid R., Sendnter M., Raff M. C. Multiple extracellular signals are required for long-term oligodendrocyte survival. Development. 1993 May;118(1):283–295. doi: 10.1242/dev.118.1.283. [DOI] [PubMed] [Google Scholar]
  7. Beck J., Rondot P., Catinot L., Falcoff E., Kirchner H., Wietzerbin J. Increased production of interferon gamma and tumor necrosis factor precedes clinical manifestation in multiple sclerosis: do cytokines trigger off exacerbations? Acta Neurol Scand. 1988 Oct;78(4):318–323. doi: 10.1111/j.1600-0404.1988.tb03663.x. [DOI] [PubMed] [Google Scholar]
  8. Bergsteindottir K., Brennan A., Jessen K. R., Mirsky R. In the presence of dexamethasone, gamma interferon induces rat oligodendrocytes to express major histocompatibility complex class II molecules. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9054–9058. doi: 10.1073/pnas.89.19.9054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Carmichael J., DeGraff W. G., Gazdar A. F., Minna J. D., Mitchell J. B. Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res. 1987 Feb 15;47(4):936–942. [PubMed] [Google Scholar]
  10. Compston A., Scolding N., Wren D., Noble M. The pathogenesis of demyelinating disease: insights from cell biology. Trends Neurosci. 1991 May;14(5):175–182. doi: 10.1016/0166-2236(91)90099-g. [DOI] [PubMed] [Google Scholar]
  11. Dawson T. M., Bredt D. S., Fotuhi M., Hwang P. M., Snyder S. H. Nitric oxide synthase and neuronal NADPH diaphorase are identical in brain and peripheral tissues. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7797–7801. doi: 10.1073/pnas.88.17.7797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Eitan S., Zisling R., Cohen A., Belkin M., Hirschberg D. L., Lotan M., Schwartz M. Identification of an interleukin 2-like substance as a factor cytotoxic to oligodendrocytes and associated with central nervous system regeneration. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5442–5446. doi: 10.1073/pnas.89.12.5442. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gard A. L., Pfeiffer S. E. Two proliferative stages of the oligodendrocyte lineage (A2B5+O4- and O4+GalC-) under different mitogenic control. Neuron. 1990 Nov;5(5):615–625. doi: 10.1016/0896-6273(90)90216-3. [DOI] [PubMed] [Google Scholar]
  14. Gavrieli Y., Sherman Y., Ben-Sasson S. A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. doi: 10.1083/jcb.119.3.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Giulian D., Baker T. J. Characterization of ameboid microglia isolated from developing mammalian brain. J Neurosci. 1986 Aug;6(8):2163–2178. doi: 10.1523/JNEUROSCI.06-08-02163.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Grau G. E., Fajardo L. F., Piguet P. F., Allet B., Lambert P. H., Vassalli P. Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria. Science. 1987 Sep 4;237(4819):1210–1212. doi: 10.1126/science.3306918. [DOI] [PubMed] [Google Scholar]
  17. Griffin D. E., Moser H. W., Mendoza Q., Moench T. R., O'Toole S., Moser A. B. Identification of the inflammatory cells in the central nervous system of patients with adrenoleukodystrophy. Ann Neurol. 1985 Dec;18(6):660–664. doi: 10.1002/ana.410180606. [DOI] [PubMed] [Google Scholar]
  18. Hafler D. A., Weiner H. L. T cells in multiple sclerosis and inflammatory central nervous system diseases. Immunol Rev. 1987 Dec;100:307–332. doi: 10.1111/j.1600-065x.1987.tb00537.x. [DOI] [PubMed] [Google Scholar]
  19. Hauser S. L., Bhan A. K., Gilles F., Kemp M., Kerr C., Weiner H. L. Immunohistochemical analysis of the cellular infiltrate in multiple sclerosis lesions. Ann Neurol. 1986 Jun;19(6):578–587. doi: 10.1002/ana.410190610. [DOI] [PubMed] [Google Scholar]
  20. Hirano A., Dembitzer H. M., Becker N. H., Levine S., Zimmerman H. M. Fine structural alterations of the blood-brain barrier in experimental allergic encephalomyelitis. J Neuropathol Exp Neurol. 1970 Jul;29(3):432–440. doi: 10.1097/00005072-197007000-00007. [DOI] [PubMed] [Google Scholar]
  21. Hope B. T., Michael G. J., Knigge K. M., Vincent S. R. Neuronal NADPH diaphorase is a nitric oxide synthase. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2811–2814. doi: 10.1073/pnas.88.7.2811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Imamura K., Suzumura A., Hayashi F., Marunouchi T. Cytokine production by peripheral blood monocytes/macrophages in multiple sclerosis patients. Acta Neurol Scand. 1993 Apr;87(4):281–285. doi: 10.1111/j.1600-0404.1993.tb05508.x. [DOI] [PubMed] [Google Scholar]
  23. Kerr J. F., Wyllie A. H., Currie A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972 Aug;26(4):239–257. doi: 10.1038/bjc.1972.33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Linnington C., Webb M., Woodhams P. L. A novel myelin-associated glycoprotein defined by a mouse monoclonal antibody. J Neuroimmunol. 1984 Sep-Oct;6(6):387–396. doi: 10.1016/0165-5728(84)90064-x. [DOI] [PubMed] [Google Scholar]
  25. Louis J. C., Magal E., Takayama S., Varon S. CNTF protection of oligodendrocytes against natural and tumor necrosis factor-induced death. Science. 1993 Jan 29;259(5095):689–692. doi: 10.1126/science.8430320. [DOI] [PubMed] [Google Scholar]
  26. Maimone D., Gregory S., Arnason B. G., Reder A. T. Cytokine levels in the cerebrospinal fluid and serum of patients with multiple sclerosis. J Neuroimmunol. 1991 Apr;32(1):67–74. doi: 10.1016/0165-5728(91)90073-g. [DOI] [PubMed] [Google Scholar]
  27. McCarthy K. D., de Vellis J. Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol. 1980 Jun;85(3):890–902. doi: 10.1083/jcb.85.3.890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Merrill J. E., Ignarro L. J., Sherman M. P., Melinek J., Lane T. E. Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide. J Immunol. 1993 Aug 15;151(4):2132–2141. [PubMed] [Google Scholar]
  29. Oka A., Belliveau M. J., Rosenberg P. A., Volpe J. J. Vulnerability of oligodendroglia to glutamate: pharmacology, mechanisms, and prevention. J Neurosci. 1993 Apr;13(4):1441–1453. doi: 10.1523/JNEUROSCI.13-04-01441.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Panitch H. S., Hirsch R. L., Haley A. S., Johnson K. P. Exacerbations of multiple sclerosis in patients treated with gamma interferon. Lancet. 1987 Apr 18;1(8538):893–895. doi: 10.1016/s0140-6736(87)92863-7. [DOI] [PubMed] [Google Scholar]
  31. Patneau D. K., Wright P. W., Winters C., Mayer M. L., Gallo V. Glial cells of the oligodendrocyte lineage express both kainate- and AMPA-preferring subtypes of glutamate receptor. Neuron. 1994 Feb;12(2):357–371. doi: 10.1016/0896-6273(94)90277-1. [DOI] [PubMed] [Google Scholar]
  32. Paty D. W., Li D. K. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Neurology. 1993 Apr;43(4):662–667. doi: 10.1212/wnl.43.4.662. [DOI] [PubMed] [Google Scholar]
  33. Pende M., Holtzclaw L. A., Curtis J. L., Russell J. T., Gallo V. Glutamate regulates intracellular calcium and gene expression in oligodendrocyte progenitors through the activation of DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3215–3219. doi: 10.1073/pnas.91.8.3215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Prineas J. W., Kwon E. E., Goldenberg P. Z., Ilyas A. A., Quarles R. H., Benjamins J. A., Sprinkle T. J. Multiple sclerosis. Oligodendrocyte proliferation and differentiation in fresh lesions. Lab Invest. 1989 Nov;61(5):489–503. [PubMed] [Google Scholar]
  35. Raff M. C., Miller R. H., Noble M. A glial progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture medium. Nature. 1983 Jun 2;303(5916):390–396. doi: 10.1038/303390a0. [DOI] [PubMed] [Google Scholar]
  36. Raff M. C., Mirsky R., Fields K. L., Lisak R. P., Dorfman S. H., Silberberg D. H., Gregson N. A., Leibowitz S., Kennedy M. C. Galactocerebroside is a specific cell-surface antigenic marker for oligodendrocytes in culture. Nature. 1978 Aug 24;274(5673):813–816. [PubMed] [Google Scholar]
  37. Raff M. C. Social controls on cell survival and cell death. Nature. 1992 Apr 2;356(6368):397–400. doi: 10.1038/356397a0. [DOI] [PubMed] [Google Scholar]
  38. Raine C. S., Scheinberg L., Waltz J. M. Multiple sclerosis. Oligodendrocyte survival and proliferation in an active established lesion. Lab Invest. 1981 Dec;45(6):534–546. [PubMed] [Google Scholar]
  39. Rosenbaum D. M., Michaelson M., Batter D. K., Doshi P., Kessler J. A. Evidence for hypoxia-induced, programmed cell death of cultured neurons. Ann Neurol. 1994 Dec;36(6):864–870. doi: 10.1002/ana.410360610. [DOI] [PubMed] [Google Scholar]
  40. Salonen R. CSF and serum interferon in multiple sclerosis: longitudinal study. Neurology. 1983 Dec;33(12):1604–1606. doi: 10.1212/wnl.33.12.1604. [DOI] [PubMed] [Google Scholar]
  41. Scolding N. J., Morgan B. P., Houston W. A., Linington C., Campbell A. K., Compston D. A. Vesicular removal by oligodendrocytes of membrane attack complexes formed by activated complement. Nature. 1989 Jun 22;339(6226):620–622. doi: 10.1038/339620a0. [DOI] [PubMed] [Google Scholar]
  42. Selmaj K. W., Raine C. S. Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro. Ann Neurol. 1988 Apr;23(4):339–346. doi: 10.1002/ana.410230405. [DOI] [PubMed] [Google Scholar]
  43. Simmons R. D., Willenborg D. O. Direct injection of cytokines into the spinal cord causes autoimmune encephalomyelitis-like inflammation. J Neurol Sci. 1990 Dec;100(1-2):37–42. doi: 10.1016/0022-510x(90)90010-k. [DOI] [PubMed] [Google Scholar]
  44. Traugott U., Lebon P. Interferon-gamma and Ia antigen are present on astrocytes in active chronic multiple sclerosis lesions. J Neurol Sci. 1988 Apr;84(2-3):257–264. doi: 10.1016/0022-510x(88)90130-x. [DOI] [PubMed] [Google Scholar]
  45. Traugott U., Reinherz E. L., Raine C. S. Multiple sclerosis: distribution of T cell subsets within active chronic lesions. Science. 1983 Jan 21;219(4582):308–310. doi: 10.1126/science.6217550. [DOI] [PubMed] [Google Scholar]
  46. Vass K., Heininger K., Schäfer B., Linington C., Lassmann H. Interferon-gamma potentiates antibody-mediated demyelination in vivo. Ann Neurol. 1992 Aug;32(2):198–206. doi: 10.1002/ana.410320212. [DOI] [PubMed] [Google Scholar]
  47. Vaux D. L. Toward an understanding of the molecular mechanisms of physiological cell death. Proc Natl Acad Sci U S A. 1993 Feb 1;90(3):786–789. doi: 10.1073/pnas.90.3.786. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Weller M., Stevens A., Sommer N., Melms A., Dichgans J., Wiethölter H. Comparative analysis of cytokine patterns in immunological, infectious, and oncological neurological disorders. J Neurol Sci. 1991 Aug;104(2):215–221. doi: 10.1016/0022-510x(91)90313-v. [DOI] [PubMed] [Google Scholar]
  49. Williams G. T., Smith C. A. Molecular regulation of apoptosis: genetic controls on cell death. Cell. 1993 Sep 10;74(5):777–779. doi: 10.1016/0092-8674(93)90457-2. [DOI] [PubMed] [Google Scholar]
  50. Wren D. R., Noble M. Oligodendrocytes and oligodendrocyte/type-2 astrocyte progenitor cells of adult rats are specifically susceptible to the lytic effects of complement in absence of antibody. Proc Natl Acad Sci U S A. 1989 Nov;86(22):9025–9029. doi: 10.1073/pnas.86.22.9025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Wren D., Wolswijk G., Noble M. In vitro analysis of the origin and maintenance of O-2Aadult progenitor cells. J Cell Biol. 1992 Jan;116(1):167–176. doi: 10.1083/jcb.116.1.167. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Molecular Medicine are provided here courtesy of The Feinstein Institute for Medical Research at North Shore LIJ

RESOURCES