| Author |
Milikovsky, Dan Z. Weissberg, Itai Levy, Nitzan Friedman, Alon Abutbul, Shai Vinogradov, Ekaterina Ketzef, Maya Fleidervish, Ilya Monsonego, Alon David, Yaron Baranauskas, Gytis Kamintsky, Lyn |
| Description |
Country affiliation: Belgium Author Affiliation: Levy N ( Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel); Milikovsky DZ ( Department of Physiology and Cell Biology, Faculty of Health Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel: and.); Baranauskas G ( Department of Physiology and Cell Biology, Faculty of Health Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel: and.); Vinogradov E ( Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel); David Y ( Department of Physiology and Cell Biology, Faculty of Health Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel: and.); Ketzef M ( Department of Physiology and Cell Biology, Faculty of Health Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel: and.); Abutbul S ( Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel); Weissberg I ( Department of Physiology and Cell Biology, Faculty of Health Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel: and.); Kamintsky L ( Department of Physiology and Cell Biology, Faculty of Health Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel: and.); Fleidervish I ( Department of Physiology and Cell Biology, Faculty of Health Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel: and.); Friedman A ( Department of Physiology and Cell Biology, Faculty of Health Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel: and Department of Medical Neuroscience, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.); Monsonego A ( Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel) |
| Abstract |
TGF-ß1 is a master cytokine in immune regulation, orchestrating both pro- and anti-inflammatory reactions. Recent studies show that whereas TGF-ß1 induces a quiescent microglia phenotype, it plays a pathogenic role in the neurovascular unit and triggers neuronal hyperexcitability and epileptogenesis. In this study, we show that, in primary glial cultures, TGF-ß signaling induces rapid upregulation of the cytokine IL-6 in astrocytes, but not in microglia, via enhanced expression, phosphorylation, and nuclear translocation of SMAD2/3. Electrophysiological recordings show that administration of IL-6 increases cortical excitability, culminating in epileptiform discharges in vitro and spontaneous seizures in C57BL/6 mice. Intracellular recordings from layer V pyramidal cells in neocortical slices obtained from IL-6 -: treated mice show that during epileptogenesis, the cells respond to repetitive orthodromic activation with prolonged after-depolarization with no apparent changes in intrinsic membrane properties. Notably, TGF-ß1 -: induced IL-6 upregulation occurs in brains of FVB/N but not in brains of C57BL/6 mice. Overall, our data suggest that TGF-ß signaling in the brain can cause astrocyte activation whereby IL-6 upregulation results in dysregulation of astrocyte -: neuronal interactions and neuronal hyperexcitability. Whereas IL-6 is epileptogenic in C57BL/6 mice, its upregulation by TGF-ß1 is more profound in FVB/N mice characterized as a relatively more susceptible strain to seizure-induced cell death. |
