TNF-alpha preconditioning protects neurons via neuron-specific up-regulation of CREB-binding protein

J Immunol. 2009 Aug 1;183(3):2068-78. doi: 10.4049/jimmunol.0801892. Epub 2009 Jul 13.


Despite being a proinflammatory cytokine, TNF-alpha preconditions neurons against various toxic insults. However, underlying molecular mechanisms are poorly understood. The present study identifies the importance of CREB-binding protein (CBP) in facilitating TNF-alpha-mediated preconditioning in neurons. Treatment of rat primary neurons with fibrillar amyloid beta1-42 (Abeta) resulted in the loss of CBP protein. However, this loss was compensated by TNF-alpha preconditioning as the expression of neuronal CBP was up-regulated in response to TNF-alpha treatment. The induction of CBP by TNF-alpha was observed only in neurons, but not in astroglia and microglia, and it was contingent on the activation of transcription factor NF-kappaB. Interestingly, antisense knockdown of CBP abrogated the TNF-alpha-mediated preconditioning of neurons against Abeta and glutamate toxicity. Similarly in vivo, preadministration of TNF-alpha in mouse neocortex prevented Abeta-induced apoptosis and loss of choline acetyltransferase-positive cholinergic neurons. However, coadministration of cbp antisense, but not scrambled oligonucleotides, negated the protective effect of TNF-alpha against Abeta neurotoxicity. This study illustrates a novel biological role of TNF-alpha in increasing neuron-specific expression of CBP for preconditioning that may have therapeutic potential against neurodegenerative disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / pharmacology
  • Animals
  • CREB-Binding Protein / genetics*
  • Cells, Cultured
  • NF-kappa B / metabolism
  • Neocortex
  • Neurons / cytology
  • Neurons / drug effects*
  • Neuroprotective Agents / pharmacology*
  • Rats
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Up-Regulation


  • Amyloid beta-Peptides
  • NF-kappa B
  • Neuroprotective Agents
  • Tumor Necrosis Factor-alpha
  • CREB-Binding Protein