title: Differential TGF-β Signaling in Glial Subsets Underlies IL-6-Mediated Epileptogenesis in Mice.
abstract: TGF-β1 is a master cytokine in immune regulation, orchestrating both pro- and anti-inflammatory reactions. Recent studies show that whereas TGF-β1 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-β 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-β1 -: induced IL-6 upregulation occurs in brains of FVB/N but not in brains of C57BL/6 mice. Overall, our data suggest that TGF-β 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-β1 is more profound in FVB/N mice characterized as a relatively more susceptible strain to seizure-induced cell death.
authors.affiliation: 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; 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.
authors.forename: Nitzan
authors.initials: N
authors.lastname: Levy
authors.affiliation: 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.
authors.forename: Dan Z
authors.initials: DZ
authors.lastname: Milikovsky
authors.affiliation: 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.
authors.forename: Gytis
authors.initials: G
authors.lastname: Baranauskas
authors.affiliation: 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;
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Vinogradov
authors.affiliation: 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.
authors.forename: Yaron
authors.initials: Y
authors.lastname: David
authors.affiliation: 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.
authors.forename: Maya
authors.initials: M
authors.lastname: Ketzef
authors.affiliation: 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;
authors.forename: Shai
authors.initials: S
authors.lastname: Abutbul
authors.affiliation: 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.
authors.forename: Itai
authors.initials: I
authors.lastname: Weissberg
authors.affiliation: 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.
authors.forename: Lyn
authors.initials: L
authors.lastname: Kamintsky
authors.affiliation: 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.
authors.forename: Ilya
authors.initials: I
authors.lastname: Fleidervish
authors.affiliation: 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.
authors.forename: Alon
authors.initials: A
authors.lastname: Friedman
authors.affiliation: 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; alonmon@bgu.ac.il.
authors.forename: Alon
authors.initials: A
authors.lastname: Monsonego
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004569:Electroencephalography; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D015850:Interleukin-6; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta