Induction of interleukin-6 by depolarization of neurons

J Neurosci. 2000 Dec 1;20(23):8637-42. doi: 10.1523/JNEUROSCI.20-23-08637.2000.

Abstract

Interleukin-6 (IL-6) has neuromodulatory and neuroprotective effects in vivo. It is expressed in glial cells and neurons both under physiological conditions and in various neurological diseases. Although the expression of IL-6 in glia has been intensely investigated, little is known about the regulation of IL-6 production by neurons. Therefore, we investigated the regulation of IL-6 expression in neurons. Membrane depolarization raised IL-6 mRNA accumulation in primary cortical cells and the PC-12 cell line. In vivo, IL-6 mRNA in the brain increased significantly after epileptic seizures. To investigate IL-6 gene transcription, PC-12 cells were transfected with reporter gene constructs containing the human IL-6 promoter. Membrane depolarization raised IL-6 transcription twofold to fourfold. This increase could be blocked by lowering extracellular Ca(2+) levels or by inhibiting L-type Ca(2+) channels or Ca(2+)/calmodulin-dependent protein kinases. Internal mutations in various elements of the IL-6 promoter revealed the glucocorticoid response element (GRE) 2 to be a depolarization-responsive element. Although the GRE2 bound the glucocorticoid receptor (GR) and was stimulated by dexamethasone, the GR was not responsible for the effect of membrane depolarization because a consensus GRE did not mediate stimulation by membrane depolarization. Instead, another yet undefined factor that binds to the IL-6 GRE2 may mediate the response to membrane depolarization. These data demonstrate that the expression of IL-6 in neurons is regulated by membrane depolarization and suggest a novel Ca(2+)-responsive promoter element. Through this mechanism, IL-6 may function as a neuromodulator induced by neuronal activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, L-Type / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Dexamethasone / pharmacology
  • Extracellular Space / metabolism
  • Gene Expression Regulation / physiology*
  • Genes, Reporter
  • Interleukin-6 / genetics*
  • Interleukin-6 / metabolism*
  • Male
  • Mice
  • Mutagenesis, Site-Directed
  • Neurons / cytology
  • Neurons / metabolism*
  • PC12 Cells
  • Potassium / metabolism
  • Potassium / pharmacology
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Receptors, Glucocorticoid / metabolism
  • Regulatory Sequences, Nucleic Acid / drug effects
  • Regulatory Sequences, Nucleic Acid / genetics
  • Transcription, Genetic / drug effects
  • Transfection

Substances

  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • Interleukin-6
  • RNA, Messenger
  • Receptors, Glucocorticoid
  • Dexamethasone
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Potassium
  • Calcium