Activation of nuclear factor-kappaB via endogenous tumor necrosis factor alpha regulates survival of axotomized adult sensory neurons.
Embryonic dorsal root ganglion (DRG) neurons die after axonal damage in vivo, and cultured embryonic DRG neurons require exogenous neurotrophic factors that activate the neuroprotective transcription factor nuclear factor-kappaB (NF-kappaB) for survival. In contrast, adult DRG neurons survive permanent axotomy in vivo and in defined culture media devoid of exogenous neurotrophic factors in vitro. Peripheral axotomy in adult rats induces local accumulation of the cytokine tumor necrosis factor alpha (TNFalpha), a potent activator of NF-kappaB activity. We tested the hypothesis that activation of NF-kappaB stimulated by endogenous TNFalpha was required for survival of axotomized adult sensory neurons. Peripheral axotomy of lumbar DRG neurons by sciatic nerve crush induced a very rapid (within 2 h) and significant elevation in NF-kappaB-binding activity. This phenomenon was mimicked in cultured neurons in which there was substantial NF-kappaB nuclear translocation and a significant rise in NF-kappaB DNA-binding activity after plating. Inhibitors of NF-kappaB (SN50 or NF-kappaB decoy DNA) resulted in necrotic cell death of medium to large neurons (> or =40 microm) within 24 h (60 and 75%, respectively), whereas inhibition of p38 and mitogen-activated protein/extracellular signal-regulated kinase did not effect survival. ELISA revealed that these cultures contained TNFalpha, and exposure to an anti-TNFalpha antibody inhibited NF-kappaB DNA-binding activity by approximately 35% and killed approximately 40% of medium to large neurons within 24 h. The results show for the first time that cytokine-mediated activation of NF-kappaB is a component of the signaling pathway responsible for maintenance of adult sensory neuron survival after axon damage.
Fernyhough
Paul
P
Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada R2H 2A6.
Smith
Darrell R
DR
Schapansky
Jason
J
Van Der Ploeg
Randy
R
Gardiner
Natalie J
NJ
Tweed
Christopher W
CW
Kontos
Andreas
A
Freeman
Lyle
L
Purves-Tyson
Tertia D
TD
Glazner
Gordon W
GW
D000818:Animals; D019898:Autocrine Communication; D019771:Axotomy; D002470:Cell Survival; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology; D020672:I-kappa B Proteins / Q000235:genetics; D020935:MAP Kinase Signaling System; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009409:Nerve Crush; D009410:Nerve Degeneration; D009475:Neurons, Afferent / Q000166:cytology / Q000187:drug effects*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D019899:Paracrine Communication; D010455:Peptides / Q000494:pharmacology; D011485:Protein Binding; D021122:Protein Subunits; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000293:injuries; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D020672:I-kappa B Proteins; D016328:NF-kappa B; D020319:Oligodeoxyribonucleotides, Antisense; D010455:Peptides; D021122:Protein Subunits; C118258:SN50 peptide; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D048051:p38 Mitogen-Activated Protein Kinases
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