Up-regulation of BDNF in astrocytes by TNF-alpha: a case for the neuroprotective role of cytokine

J Neuroimmune Pharmacol. 2006 Sep;1(3):212-22. doi: 10.1007/s11481-006-9020-8. Epub 2006 May 16.


Tumor necrosis factor-alpha (TNF-alpha) is widely known to be involved in physiological and pathophysiological processes of the brain where this proinflammatory cytokine is implicated with regulation of inflammatory and survival components. We report that TNF-alpha up-regulates exon-IV-bdnf mRNA and brain-derived neurotrophic factor (BDNF) protein in primary astrocytes. The BDNF protein was detectable both in cellular lysate and in the extracellular medium. Activation of NF-kappaB by TNF-alpha and inhibition of TNF-alpha-induced BDNF expression by Deltap65 (a dominant-negative mutant) and NEMO-binding domain peptide (an inhibitor of NF-kappaB) suggests that TNF-alpha induces BDNF expression through the activation of NF-kappaB. Similarly, TNF-alpha induced the activation of C/EBPbeta and the expression of BDNF was sensitive to overexpression of DeltaC/EBPbeta (a dominant-negative mutant) and ETO (an inhibitor of C/EBPbeta). Among three MAP kinases, TNF-alpha-induced BDNF up-regulation was sensitive only to inhibitors of ERK MAP kinase. However, the ERK MAP kinase pathway was coupled to activation of C/EBPbeta but not NF-kappaB. Taken together, this study identifies a novel property of TNF-alpha in inducing the expression of BDNF via NF-kappaB and C/EBPbeta in astrocytes that may be responsible for neurotrophic activity of the cytokine.

Publication types

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

MeSH terms

  • Animals
  • Astrocytes / metabolism*
  • Blotting, Western
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Cells, Cultured
  • Cytokines / metabolism
  • Electrophoretic Mobility Shift Assay
  • Enzyme-Linked Immunosorbent Assay
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression
  • Immunohistochemistry
  • NF-kappa B / metabolism
  • Neuroimmunomodulation / physiology*
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / metabolism*
  • Up-Regulation


  • Brain-Derived Neurotrophic Factor
  • Cytokines
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Extracellular Signal-Regulated MAP Kinases