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Administration of tumour necrosis factor α (TNFα) to axotomised mouse neonatal sciatic nerves increased Schwann cell apoptosis in the distal nerve segments, 5-fold greater than axotomy alone. TNFα upregulated the low affinity neurotrophin receptor, p75NTR, indicative of phenotype reversion in Schwann cells. Furthermore, re-expression of p75NTR and downregulation of the pro-myelinating transcription factor, Oct 6, in Schwann cells occurred by treatment with TNFα, even after the maturation of these cells with brain derived neurotrophic factor (BDNF). TNFα treatment of Schwann cells produced only a transient activation of NFκB. More importantly, in NFκB (p65) mutant mice, axotomy increased Schwann cell apoptosis further than that seen in mice expressing NFκB (p65), implicating a survival role for NFκB. Collectively, these data suggest that TNFα can potentiate Schwann cell death through the modulation of their phenotype. Immature Schwann cells express a high level of p75NTR and as a consequence are susceptible to extracellular death stimuli because of the lack of sustained NFκB translocation.