Type I interferons impair BDNF-induced cell signaling and neurotrophic activity in differentiated human SH-SY5Y neuroblastoma cells and mouse primary cortical neurons

J Neurochem. 2012 Jul;122(1):58-71. doi: 10.1111/j.1471-4159.2012.07766.x. Epub 2012 May 21.

Abstract

Type I interferons (IFNs) have been shown to act on neurons and to cause neuronal damage through mechanisms not completely defined. Here, we investigated the effects of type I IFNs on brain-derived neurotrophic factor (BDNF)-induced TrkB receptor signaling and neurotrophic activity. In retinoic acid-treated human SH-SY5Y neuroblastoma cells and mouse primary cortical neurons, long-term exposure to IFNs curtailed BDNF-induced activation of phosphatidylinositol 3-kinase, phospholipase Cγ and extracellular-regulated kinases 1 and 2 signaling. Moreover, IFN-β inhibited BDNF-induced cell survival, neurite outgrowth, and expression of neuronal markers, such as neurofilament proteins, growth-associated protein-43 and glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor subunit GluR1. The IFN inhibitory effects were associated with down-regulation of TrkB and inhibition of TrkB autophosphorylation. In SH-SY5Y cells, blockade of either Janus kinase with pyridone 6 or signal transducer and activator of transcription (STAT) 1 with siRNA transfection attenuated IFN-β-induced TrkB down-regulation. Quantitative real time RT-PCR indicated that IFN-β significantly reduced TrkB mRNA levels. Moreover, blockade of protein kinase R counteracted IFN-β-induced inhibition of TrkB expression and signaling. These data indicate that in neuronal cells IFNs negatively regulate BDNF signaling and neurotrophic activity through inhibition of TrkB activation and Janus kinase/Signal transducer and activator of transcription-dependent down-regulation of TrkB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Brain-Derived Neurotrophic Factor / pharmacology*
  • Cell Differentiation / drug effects*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Drug Interactions
  • Female
  • Frontal Lobe / cytology*
  • Gene Expression Regulation / drug effects
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Interferon Type I / pharmacology*
  • Male
  • Mice
  • Muscarinic Agonists / pharmacology
  • Neuroblastoma / pathology
  • Neurogenesis / drug effects
  • Neurons / drug effects*
  • Neurons / metabolism
  • Oncogene Protein v-akt / metabolism
  • Oxotremorine / analogs & derivatives
  • Oxotremorine / pharmacology
  • Phosphorylation / drug effects
  • RNA, Small Interfering / metabolism
  • Signal Transduction / drug effects*
  • Transfection

Substances

  • Brain-Derived Neurotrophic Factor
  • Interferon Type I
  • Muscarinic Agonists
  • RNA, Small Interfering
  • Oxotremorine
  • oxotremorine M
  • Glycogen Synthase Kinase 3 beta
  • Oncogene Protein v-akt
  • Glycogen Synthase Kinase 3