Neuroprotective actions of endogenous interleukin-1 receptor antagonist (IL-1ra) are mediated by glia.
The pro-inflammatory cytokine interleukin-1 (IL-1), contributes to neuronal inflammation and cell death induced by ischemia, excitotoxicity, or trauma, while administration of IL-1 receptor antagonist (IL-1ra) reduces neuronal injury. The aim of the present study was to test the hypothesis that endogenous IL-1ra is neuroprotective in vivo and in vitro, and to identify its mechanism of actions. Mice lacking IL-1ra (IL-1ra knock-out (KO]) exhibited a dramatic increase in neuronal injury (3.6-fold increase in infarct size) induced by transient cerebral ischemia compared to wild-type (WT) animals. Basal cell death of cultured cortical neurons from WT and IL-1ra KO was identical, and treatment with NMDA or AMPA (20 microM) increased cell death to the same extent in WT and IL-1ra KO neurons. However, basal and NMDA- or AMPA-induced cells death was significantly higher in glial-neuronal co-cultures from IL-1ra KO than from WT mice. We further showed that pure microglial cultures, but not pure astrocytes cultures, released IL-1ra in response to treatment with conditioned medium from NMDA- or AMPA-treated primary neurons. These results demonstrate that endogenous IL-1ra produced by microglia is neuroprotective in cerebral ischemia or excitotoxicity.
Pinteaux
Emmanuel
E
Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester, United Kingdom.
Rothwell
Nancy J
NJ
Boutin
Herve
H
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000473:pathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D053590:Interleukin 1 Receptor Antagonist Protein; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents; D010477:Perfusion; D012795:Sialoglycoproteins / Q000494:pharmacology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
D017077:Culture Media, Conditioned; D018690:Excitatory Amino Acid Agonists; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D018696:Neuroprotective Agents; D012795:Sialoglycoproteins; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid