Ali C. Nicole O. Docagne F. Lesne S. MacKenzie ET. Nouvelot A. Buisson A. Vivien D.
Ischemia-induced interleukin-6 as a potential endogenous neuroprotective
cytokine against NMDA receptor-mediated excitotoxicity in the brain, Journal of Cerebral Blood Flow & Metabolism 20(6) :956-66, 2000.
Abstract
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.
Important Points:
-Model: in vivo rat, cortical culture
-Ischemia and NMDA treatment up-regulate IL-6 mRNA
-neurons may produce IL-6 in response to the calcium influx through NMDA receptors
-IL-6 protected neurons against NMDA toxicity in culture in a dose-dependent manner
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