TNFα mediates Schwann cell death by upregulating p75NTR expression without sustained activation of NFκB

Administration of tumour necrosis factor alpha (TNF alpha) to axotomised mouse neonatal sciatic nerves increased Schwann cell apoptosis in the distal nerve segments, 5-fold greater than axotomy alone. TNF alpha upregulated the low affinity neurotrophin receptor, p75(NTR), indicative of phenotype reversion in Schwann cells. Furthermore, re-expression of p75(NTR) and downregulation of the pro-myelinating transcription factor, Oct 6, in Schwann cells occurred by treatment with TNF alpha, even after the maturation of these cells with brain derived neurotrophic factor (BDNF). TNF alpha treatment of Schwann cells produced only a transient activation of NF kappa B. More importantly, in NF kappa B (p65) mutant mice, axotomy increased Schwann cell apoptosis further than that seen in mice expressing NF kappa B (p65), implicating a survival role for NF kappa B. Collectively, these data suggest that TNF alpha can potentiate Schwann cell death through the modulation of their phenotype. Immature Schwann cells express a high level of p75(NTR) and as a consequence are susceptible to extracellular death stimuli because of the lack of sustained NF kappa B translocation. (c) 2005 Elsevier Inc. All rights reserved.