Ischemia-induced interleukin-6 as a potential endogenous neuroprotective cytokine against NMDA receptor-mediated excitotoxicity in the brain.
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.
Ali
C
C
Université de Caen, UMR-CNRS 6551, IFR 47, France.
Nicole
O
O
Docagne
F
F
Lesne
S
S
MacKenzie
E T
ET
Nouvelot
A
A
Buisson
A
A
Vivien
D
D
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001253:Astrocytes / Q000166:cytology; D001923:Brain Chemistry / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000098:blood supply / Q000166:cytology / Q000276:immunology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D020244:Infarction, Middle Cerebral Artery / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D002546:Ischemic Attack, Transient / Q000276:immunology*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000276:immunology; D018696:Neuroprotective Agents / Q000276:immunology*; D009498:Neurotoxins / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000502:physiology; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000276:immunology; D018092:Kainic Acid Receptors / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D014158:Transcription, Genetic / Q000276:immunology
D018690:Excitatory Amino Acid Agonists; D015850:Interleukin-6; D015759:Ionomycin; D007476:Ionophores; D016202:N-Methylaspartate; D018696:Neuroprotective Agents; D009498:Neurotoxins; D012333:RNA, Messenger; D018091:Receptors, AMPA; D019947:Receptors, Interleukin-6; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate