Interleukin-6 inhibits neurotransmitter release and the spread of excitation in the rat cerebral cortex.
Cytokines are extracellular mediators that have been reported to affect neurotransmitter release and synaptic plasticity phenomena when applied in vitro. Most of these effects occur rapidly after the application of the cytokines and are presumably mediated through the activation of protein phosphorylation processes. While many cytokines have an inflammatory action, interleukin-6 (IL-6) has been found to have a neuroprotective effect against ischaemia lesions and glutamate excitotoxicity, and to increase neuronal survival in a variety of experimental conditions. In this paper, the functional effects of IL-6 on the spread of excitation visualized by dark-field/infrared videomicroscopy in rat cortical slices and on glutamate release from cortical synaptosomes were analysed and correlated with the activation of the STAT3, mitogen-activated protein kinase ERK (MAPK/ERK) and stress-activated protein kinase/cJun NH2-terminal kinase (SAPK/JNK) pathways. We have found that IL-6 depresses the spread of excitation and evoked glutamate release in the cerebral cortex, and that these effects are accompanied by a stimulation of STAT3 tyrosine phosphorylation, an inhibition of MAPK/ERK activity, a decreased phosphorylation of the presynaptic MAPK/ERK substrate synapsin I and no detectable effects on SAPK/JNK. The effects of IL-6 were effectively counteracted by treatment of the cortical slices with the tyrosine kinase inhibitor lavendustin A. The inhibitory effects of IL-6 on glutamate release and on the spread of excitation in the rat cerebral cortex indicate that the protective effect of IL-6 on neuronal survival could be mediated by a downregulation of neuronal activity, release of excitatory neurotransmitters and MAPK/ERK activity.
D'Arcangelo
G
G
Department of Neuroscience, University of Roma Tor Vergata, Via di Tor Vergata 135, I-00133 Roma, Italy.
Tancredi
V
V
Onofri
F
F
D'Antuono
M
M
Giovedì
S
S
Benfenati
F
F
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology*; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005089:Exocytosis / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D007259:Infrared Rays; D015850:Interleukin-6 / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000032:analysis; D018715:Microscopy, Video / Q000379:methods; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D010766:Phosphorylation; D017729:Presynaptic Terminals / Q000737:chemistry / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor; D016704:Synapsins / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D013574:Synaptosomes / Q000187:drug effects / Q000201:enzymology; D015534:Trans-Activators / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D015703:Antigens, CD; D004268:DNA-Binding Proteins; C494201:Il6st protein, rat; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D016704:Synapsins; D015534:Trans-Activators; D050822:Cytokine Receptor gp130; D018698:Glutamic Acid; D014443:Tyrosine; D048056:Mitogen-Activated Protein Kinase 9; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases