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

• Published in: Journal of cerebral blood flow and metabolism Vol. 20; no. 6; p. 956
• Main Authors: Ali, C, Nicole, O, Docagne, F, Lesne, S, MacKenzie, E T, Nouvelot, A, Buisson, A, Vivien, D
• Format: Journal Article
• Language: English
• Published: United States 01.06.2000
• Subjects: 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; 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; RNA, Messenger - analysis; Transcription, Genetic - immunology
• ISSN: 0271-678X; 1559-7016

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.