TNFalpha mediates Schwann cell death by upregulating p75NTR expression without sustained activation of NFkappaB.
Administration of tumour necrosis factor alpha (TNFalpha) to axotomised mouse neonatal sciatic nerves increased Schwann cell apoptosis in the distal nerve segments, 5-fold greater than axotomy alone. TNFalpha 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 TNFalpha, even after the maturation of these cells with brain derived neurotrophic factor (BDNF). TNFalpha treatment of Schwann cells produced only a transient activation of NFkappaB. More importantly, in NFkappaB (p65) mutant mice, axotomy increased Schwann cell apoptosis further than that seen in mice expressing NFkappaB (p65), implicating a survival role for NFkappaB. Collectively, these data suggest that TNFalpha 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 NFkappaB translocation.
Boyle
Kristy
K
The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Post Office, The Royal Melbourne Hospital, Victoria 3050, Australia.
Azari
Michael F
MF
Cheema
Surindar S
SS
Petratos
Steven
S
D000818:Animals; D000831:Animals, Newborn; D019771:Axotomy; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D050816:Octamer Transcription Factor-6 / Q000187:drug effects / Q000378:metabolism; D010525:Peripheral Nerves / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000378:metabolism / Q000503:physiopathology; D010641:Phenotype; D011129:Polyradiculoneuropathy / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism*; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D051996:Transcription Factor RelA / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D016328:NF-kappa B; D020800:Receptor, Nerve Growth Factor; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D050816:Octamer Transcription Factor-6