A Novel Non-Transcriptional Pathway Mediates the Proconvulsive Effects of interleukin-1beta

Brain. 2008 Dec;131(Pt 12):3256-65. doi: 10.1093/brain/awn271. Epub 2008 Oct 24.

Abstract

Interleukin-1beta (IL-1beta) is overproduced in human and rodent epileptogenic tissue and it exacerbates seizures upon brain application in rodents. Moreover, pharmacological prevention of IL-1beta endogenous synthesis, or IL-1 receptor blockade, mediates powerful anticonvulsive actions indicating a significant role of this cytokine in ictogenesis. The molecular mechanisms of the proconvulsive actions of IL-1beta are not known. We show here that EEG seizures induced by intrahippocampal injection of kainic acid in C57BL6 adult mice were increased by 2-fold on average by pre-exposure to IL-1beta and this effect was blocked by 3-O-methylsphingomyelin (3-O-MS), a selective inhibitor of the ceramide-producing enzyme sphingomyelinase. C2-ceramide, a cell permeable analog of ceramide, mimicked IL-1beta action suggesting that ceramide may be the second messenger of the proconvulsive effect of IL-1beta. The seizure exacerbating effects of either IL-1beta or C2-ceramide were dependent on activation of the Src family of tyrosine kinases since they were prevented by CGP76030, an inhibitor of this enzyme family. The proconvulsive IL-1beta effect was associated with increased Tyr(418) phosphorylation of Src-family of kinases indicative of its activation, and Tyr(1472) phosphorylation of one of its substrate, the NR2B subunit of the N-methyl-d-aspartate receptor, which were prevented by 3-O-MS and CGP76030. Finally, the proconvulsive effect of IL-1beta was blocked by ifenprodil, a selective NR2B receptor antagonist. These results indicate that the proconvulsive actions of IL-1beta depend on the activation of a sphingomyelinase- and Src-family of kinases-dependent pathway in the hippocampus which leads to the phosphorylation of the NR2B subunit, thus highlighting a novel, non-transcriptional mechanism underlying seizure exacerbation in inflammatory conditions.

Publication types

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

MeSH terms

  • Animals
  • Astrocytes / metabolism
  • Ceramides / physiology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Interleukin-1beta / metabolism
  • Interleukin-1beta / physiology*
  • Interleukin-1beta / toxicity
  • Kainic Acid
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Receptors, Interleukin-1 / metabolism
  • Receptors, N-Methyl-D-Aspartate / physiology
  • Recombinant Proteins / toxicity
  • Seizures / chemically induced
  • Seizures / metabolism
  • Seizures / physiopathology*
  • Signal Transduction / drug effects
  • Sphingomyelin Phosphodiesterase / physiology
  • src-Family Kinases / physiology

Substances

  • Ceramides
  • Interleukin-1beta
  • NR2B NMDA receptor
  • Receptors, Interleukin-1
  • Receptors, N-Methyl-D-Aspartate
  • Recombinant Proteins
  • src-Family Kinases
  • Sphingomyelin Phosphodiesterase
  • Kainic Acid