Neuronal injury induces the release of pro-interleukin-1beta from activated microglia in vitro.
Microglia activated after brain injury, are a major source of the pro-inflammatory cytokine interleukin-1 (IL-1), which is known to further exacerbate damage. However, the mechanisms that control IL-1 release in acute neuronal injury are unknown and the purpose of this study was to test the hypothesis that neuronal injury induces IL-1beta release from microglial cells. Here we report that lipopolysaccharide (LPS)-activated rat microglia co-cultured with healthy rat neurons express pro-IL-1beta, which in the absence of cell death accumulates in the cells. Treatment of co-cultures with the excitotoxin N-methyl-D-aspartate (NMDA) induced neuronal cell death leading to the appearance of pro-IL-1beta in the culture supernatant. This effect was reversed by the NMDA receptor antagonist MK-801, and was neuron-dependent, since NMDA had no effect on cell death or pro-IL-1beta release in mixed glial cell cultures. In addition, we show that pro-IL-1beta release from LPS-treated mixed glia or LPS-treated microglia is significantly reduced in the presence of conditioned medium from healthy co-cultures or neuronal cultures respectively. These results demonstrate that injured neurons promote the release of pro-IL-1beta from microglia, possibly by regulating microglial cell viability, and suggest an important alternative mechanism of IL-1beta release that occurs in response to neuronal injury.
Wang
Penglian
P
Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK.
Rothwell
Nancy J
NJ
Pinteaux
Emmanuel
E
Brough
David
D
D000818:Animals; D001921:Brain / Q000166:cytology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008840:Microfilament Proteins; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric
C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; D017077:Culture Media, Conditioned; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D007770:L-Lactate Dehydrogenase