Differential TGF-β Signaling in Glial Subsets Underlies IL-6-Mediated Epileptogenesis in Mice

J Immunol. 2015 Aug 15;195(4):1713-22. doi: 10.4049/jimmunol.1401446. Epub 2015 Jul 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Brain / drug effects
  • Brain / metabolism
  • Disease Models, Animal
  • Electroencephalography
  • Epilepsy / genetics
  • Epilepsy / metabolism*
  • Epilepsy / physiopathology
  • Gene Expression Regulation / drug effects
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Mice
  • Microglia / drug effects
  • Microglia / metabolism
  • Neuroglia / metabolism*
  • Neurons / drug effects
  • Neurons / metabolism
  • Organ Specificity / genetics
  • Phosphorylation / drug effects
  • Protein Transport
  • Signal Transduction*
  • Smad2 Protein / metabolism
  • Smad3 Protein / metabolism
  • Transforming Growth Factor beta / administration & dosage
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / pharmacology

Substances

  • Interleukin-6
  • Smad2 Protein
  • Smad3 Protein
  • Transforming Growth Factor beta