Ischemia-induced interleukin-6 as a potential endogenous neuroprotective cytokine against NMDA receptor-mediated excitotoxicity in the brain

J Cereb Blood Flow Metab. 2000 Jun;20(6):956-66. doi: 10.1097/00004647-200006000-00008.


In the brain, the expression of the pleiotropic cytokine interleukin-6 (IL-6) is enhanced in various chronic or acute central nervous system disorders. However, the significance of IL-6 production in such neuropathologic states remains controversial. The present study investigated the role of IL-6 after cerebral ischemia. First, the authors showed that focal cerebral ischemia in rats early up-regulated the expression of IL-6 mRNA, without affecting the transcription of its receptors (IL-6Ralpha and gp130). Similarly, the striatal injection of N-methyl-D-aspartate (NMDA) in rats, a paradigm of excitotoxic injury, activated the expression of IL-6 mRNA. The involvement of glutamatergic receptor activation was further investigated by incubating cortical neurons with NMDA or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA). NMDA and ionomycin (a calcium ionophore) up-regulated IL-6 mRNA, suggesting that neurons may produce IL-6 in response to the calcium influx mediated through NMDA receptors. The potential role of IL-6 during ischemic/excitotoxic insults was then studied by testing the effect of IL-6 against apoptotic or excitotoxic challenges in cortical cultures. IL-6 did not prevent serum deprivation- or staurosporine-induced apoptotic neuronal death, or AMPA/kainate-mediated excitotoxicity. However, in both mixed and pure neuronal cultures, IL-6 dose-dependently protected neurons against NMDA toxicity. This effect was blocked by a competitive inhibitor of IL-6. Overall, the results suggest that the up-regulation of IL-6 induced by cerebral ischemia could represent an endogenous neuroprotective mechanism against NMDA receptor-mediated injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / immunology
  • Astrocytes / cytology
  • Brain Chemistry / drug effects
  • Brain Chemistry / immunology
  • Cells, Cultured
  • Cerebral Cortex / blood supply
  • Cerebral Cortex / cytology
  • Cerebral Cortex / immunology
  • Excitatory Amino Acid Agonists / pharmacology
  • Gene Expression / drug effects
  • Gene Expression / immunology
  • Infarction, Middle Cerebral Artery / immunology
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology*
  • Ionomycin / pharmacology
  • Ionophores / pharmacology
  • Ischemic Attack, Transient / immunology*
  • Male
  • N-Methylaspartate / pharmacology
  • Neurons / chemistry
  • Neurons / cytology
  • Neurons / immunology
  • Neuroprotective Agents / immunology*
  • Neurotoxins / pharmacology
  • Polymerase Chain Reaction
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / physiology
  • Receptors, Interleukin-6 / genetics
  • Receptors, Interleukin-6 / immunology
  • Receptors, Kainic Acid / physiology
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Transcription, Genetic / immunology


  • Excitatory Amino Acid Agonists
  • Interleukin-6
  • Ionophores
  • Neuroprotective Agents
  • Neurotoxins
  • RNA, Messenger
  • Receptors, AMPA
  • Receptors, Interleukin-6
  • Receptors, Kainic Acid
  • Receptors, N-Methyl-D-Aspartate
  • Ionomycin
  • N-Methylaspartate