Activation of Nuclear Factor-κB via Endogenous Tumor Necrosis Factor α 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-κB (NF-κB) 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 α (TNFα), a potent activator of NF-κB activity. We tested the hypothesis that activation of NF-κB stimulated by endogenous TNFα 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-κB-binding activity. This phenomenon was mimicked in cultured neurons in which there was substantial NF-κB nuclear translocation and a significant rise in NF-κB DNA-binding activity after plating. Inhibitors of NF-κB (SN50 or NF-κB decoy DNA) resulted in necrotic cell death of medium to large neurons (≥40 μm) 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 TNFα, and exposure to an anti-TNFα antibody inhibited NF-κB DNA-binding activity by ∼35% and killed ∼40% of medium to large neurons within 24 h. The results show for the first time that cytokine-mediated activation of NF-κB is a component of the signaling pathway responsible for maintenance of adult sensory neuron survival after axon damage.