Tumor Necrosis Factor Induces Bcl-2 and Bcl-x Expression through NFκB Activation in Primary Hippocampal Neurons

Emerging data indicate that tumor necrosis factor (TNF) exerts a neuroprotective effect in response to brain injury. Here we examined the mechanism of TNF in preventing neuronal death in primary hippocampal neurons. TNF protected neurons against hypoxia- or nitric oxide-induced injury, with an increase in the anti-apoptotic proteins Bcl-2 and Bcl-x as determined by Western blot and reverse transcriptase-polymerase chain reaction analysis. Treatment of neurons with an antisense oligonucleotide to bcl-2 mRNA or that to bcl-x mRNA blocked the up-regulation of Bcl-2 or Bcl-x expression, respectively, and partially inhibited the neuroprotective effect induced by TNF. Moreover, adenovirus-mediated overexpression of Bcl-2 significantly inhibited hypoxia- or nitric oxide-induced neuronal death. To examine the possible involvement of a transcription factor, NF Kappa B, in the regulation of Bcl-2 and Bcl-x expression in TNF-treated neurons, an adenoviral vector capable of expressing a mutated form of I Kappa B was used to infect neurons prior to TNF treatment. Expression of the mutant NF Kappa B completely inhibited NF Kappa B DNA binding activity and inhibited both TNF- induced up-regulation of Bcl-2 and Bcl-x expression and neuroprotective effect. These findings indicate that induction of Bcl-2 and Bcl-x expression through NF Kappa B activation is involved in the neuroprotective action of TNF against hypoxia- or nitric oxide-induced injury.