Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination

Abstract

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by localized areas of demyelination1. Although the etiology and pathogenesis of MS remain largely unknown, it is generally assumed that immune responses to myelin antigens contribute to the disease process1,2. The exact sequence of events, as well as the molecular mediators that lead to myelin destruction, is yet to be defined2,3. As a potent mediator of inflammation, the cytopathic cytokine, tumor necrosis factor (TNF) has been considered to be a strong candidate in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE)3–5. However, its role in immune-mediated demyelination remains to be elucidated. To determine the contribution of TNF to the pathogenesis of the MS-like disease provoked by the myelin oligodendrocyte glycoprotein (MOG)6, we have tested mice with an homologous disruption of the gene encoding TNF (ref. 7). Here we report that upon immunization with MOG, mice lacking TNF develop severe neurological impairment with high mortality and extensive inflammation and demyelination. We show further that inactivation of the TNF gene converts MOG-resistant mice to a state of high susceptibility. Furthermore, treatment with TNF dramatically reduces disease severity in both TNF−/− mice and in other TNF+/+ mice highly susceptible to the MOG-induced disease. These findings indicate that TNF is not essential for the induction and expression of inflammatory and demyelinating lesions, and that it may limit the extent and duration of severe CNS pathology.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Raine, C.S. The immunology of the multiple sclerosis lesion [The Dale E. McFarlin memorial lecture]. Ann. Neurol. 36, S61–S72 (1994).

    Article  CAS  Google Scholar 

  2. Bernard, C.C.A. & Kerlero de Rosbo, N. Multiple sclerosis: An autoimmune disease of multifactorial etiology. Curr. Opin. Cell Biol. 4, 760–765 (1992).

    Article  CAS  Google Scholar 

  3. Merrill, J.E. & Benveniste, E.N. Cytokines in inflammatory brain lesions: Helpful and harmful. Trends Neurosci. 19, 331–338 (1996).

    Article  CAS  Google Scholar 

  4. Navikas, V. & Link, H. Cytokines and the pathogenesis of multiple sclerosis [Review]. J. Neurosci. Res. 45, 322–333 (1996).

    Article  CAS  Google Scholar 

  5. Selmaj, K., Papierz, W., Glabinski, A. & Kohno, T. Prevention of chronic relapsing experimental autoimmune encephalomyelitis by soluble tumor necrosis factor receptor I. J. Neuroimmunol. 56, 135–141 (1995).

    Article  CAS  Google Scholar 

  6. Bernard, C.C.A., et al. Myelin oligodendrocyte glycoprotein: A novel candidate autoantigen in multiple sclerosis. J. Mol. Med. 75, 77–88 (1997).

    Article  CAS  Google Scholar 

  7. Marino, M.W., et al. Characterization of tumor necrosis factor deficient mice. Proc. Natl. Acad. Sci. USA 94, 8093–8098 (1997).

    Article  CAS  Google Scholar 

  8. Aggarwal, B.B. & Natarajan, K. Tumor necrosis factor: Developments during the last decade. Eur. Cytokine Netw. 7; 93–124 (1996).

    CAS  PubMed  Google Scholar 

  9. Ruddle, N.H. et al. An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis. J. Exp. Med. 172, 1193–1200 (1990).

    Article  CAS  Google Scholar 

  10. Willenborg, D.O., Fordham, S., Bernard, C.C.A., Cowden, W.B. & Ramshaw, I.A. IFN-γ plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocy glycoprotein-induced autoimmune encephalomyelitis. J. Immunol. 157, 3223–3227 (1996).

    CAS  PubMed  Google Scholar 

  11. Ichikawa, M., Johns, T.G., Liu, J. & Bernard, C.C.A. Analysis of the fine B cell specificity during the chronic/relapsing course of a multiple sclerosis-like disease in Lewis rats injected with the encephalitogenic myelin oligodendrocyte glycoprotein peptide 35–55. J. Immunol. 157, 919–926 (1996).

    CAS  PubMed  Google Scholar 

  12. Pasparakis, M., Alexopoulou, L., Episkopou, V. & Kollias, G. Immune and inflammatory responses in TNFα-deficient mice: A critical requirement for TNFα in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J. Exp. Med. 184, 1397–1411 (1996).

    Article  CAS  Google Scholar 

  13. Linington, C., et al. T cells specific for the myelin oligodendrocyte glycoprotein mediate an unusual autoimmune inflammatory response in the central nervous system. Eur. J. Immunol. 23, 1364–1371 (1993).

    Article  CAS  Google Scholar 

  14. Sercarz, E.E., et al. Dominance and crypticity of T cell antigenic determinants. Annu. Rev. Immunol. 11, 729–766 (1993).

    Article  CAS  Google Scholar 

  15. Selmaj, K., Raine, C.S., Farooq, M., Norton, W.T. & Brosnan, C.F. Cytokine cytotoxicity against oligodendrocytes: Apoptosis induced by lymphotoxin. J. Immunol. 147, 1522–1529 (1991).

    CAS  PubMed  Google Scholar 

  16. Sharief, M.K. & Hentges, R. Association between tumor necrosis factor-α and disease progression in patients with multiple sclerosis. N. Engl. J. Med. 325, 467–472 (1991).

    Article  CAS  Google Scholar 

  17. Paya, C.V., Leibson, P.J., Patrick, A.K. & Rodriguez, M. Inhibition of Theiler's virus-induced demyelination in vivo by tumor necrosis factor-α. Int. Immunol. 2, 909–913 (1990).

    Article  CAS  Google Scholar 

  18. Jacob, C.O. & McDevitt, H.O. Tumour necrosis factor-α in murine autoimmune ‘lupus’ nephritis. Nature, 331, 356–358 (1988).

    Article  CAS  Google Scholar 

  19. Jacob, C.O., Aiso, S., Michie, S.A., McDevitt, H.O. & Acha-Orbea, H. Prevention of diabetes in nonobese diabetic mice by tumor necrosis factor (TNF): Similarities between TNF-α and interleukin 1. Proc. Natl. Acad. Sci. USA 87, 968–972 (1990).

    Article  CAS  Google Scholar 

  20. Bruce, A.J., et al. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nature Med. 2, 788–794 (1996).

    Article  CAS  Google Scholar 

  21. Rothwell, N.J. & Luheshi, G.N. Brain TNF: Damage limitation or damaged reputation? Nature Med. 2, 746–747 (1996).

    Article  CAS  Google Scholar 

  22. Liu, Z., Hsu, H., Goeddel, D.V. & Karin, M. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-κB activation prevents cell death. Cell 87, 565–576 (1996).

    Article  CAS  Google Scholar 

  23. Eugster, H-P., et al. Multiple immune abnormalities in tumor necrosis factor and lymphotoxin-α double-deficient mice. Int. Immunol. 8, 23–36 (1996).

    Article  CAS  Google Scholar 

  24. Lewis, M., et al. Cloning and expression of cDNAs for two distinct murine tumor necrosis factor receptors demonstrate one receptor is species specific. Proc. Natl. Acad. Sci. USA 88, 2830–2834 (1991).

    Article  CAS  Google Scholar 

  25. Vanoosten, B.W., et al. Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody CA2. Neurology 47, 1531–1534 (1996).

    Article  CAS  Google Scholar 

  26. Jayaram, B.M., Menon, K.K., Slavin, A., Reid, H. & Bernard, C.C.A. Purification of human myelin oligodendrocyte glycoprotein (MOG) produced in bacteria and Sf9 insect cells [Abstr.]. J. Neurochem. 66, S41 (1996).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, J., Marino, M., Wong, G. et al. TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination. Nat Med 4, 78–83 (1998). https://doi.org/10.1038/nm0198-078

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0198-078

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing