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TNFα: kill or cure for demyelinating disease?

Molecular Psychiatry volume 7, pages 820–821 (2002)Cite this article

Tumor necrosis factor α (TNFα) is a proinflammatory, pleiotropic cytokine. It has long been implicated in the immunopathogenesis of multiple sclerosis (MS), which is an inflammatory and demyelinating disease of the CNS. Anti-TNFα directed therapies in MS, in contrast to results in the animal model experimental allergic encephalomyelitis (EAE), are reported to exacerbate disease activity.1,2 Such therapies can even trigger demyelinating disease in patients with rheumatoid arthritis, where the therapy otherwise is considered very successful.3 These contrasting effects might be explained, at least in part, by observations from experimental studies using TNF and TNF receptor knock out animals. TNFα, in addition to its pro-inflammatory and demyelinating effects, could also at physiologic levels protect tissue from injury. The study of Arnett et al4 further shows that this molecule can stimulate the differentiation of oligodendrocyte precursor cells into myelinating oligodendrocytes, thereby promoting remyelination of demyelinated lesions in CNS.

TNFα exists as a soluble non-glycosylated 17 kDa and a membrane-bound 26 kDa homotrimeric molecule in the human.5 TNFα is present at low levels in the normal CNS, and at increased levels in the inflamed or injured CNS. In patients with MS and in animals with EAE, and other degenerative conditions, TNFα mRNA and protein are associated primarily with activated microglia and infiltrating macrophages.6 TNFα acts through its two receptors, the 55 kDa (p55R, TNFR1) and the 75 kDa receptor (p75R, TNFR2).5 TNFR1 contains cytoplasmic domains that may either induce apoptosis or downstream activation of nuclear factor kappa B (NF-κB). Binding of TNFα to TNFR2 transduces growth and cellular activation signals.5 Most cell types including immune cells, endothelial cells, and neurons and glial cells have the potential to express both TNF receptors. TNF- and TNFR-deficient mice live normal lives, and their CNS develops normally, with normal numbers and distribution of neurons and glial cells, including myelinating oligodendrocytes.

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Authors and Affiliations

  1. Anatomy and Neurobiology, Institute of Medical Biology, University of Southern Denmark-Odense, Odense, Denmark

    B Finsen

  2. Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada

    J Antel & T Owens

Authors
  1. B Finsen
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  2. J Antel
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  3. T Owens
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Correspondence to B Finsen.

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Finsen, B., Antel, J. & Owens, T. TNFα: kill or cure for demyelinating disease?. Mol Psychiatry 7, 820–821 (2002). https://doi.org/10.1038/sj.mp.4001120

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