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

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.

• Authors: Simona Dedoni, Maria C Olianas, Angela Ingianni, Pierluigi Onali
• Journal: Journal of neurochemistry (J Neurochem) Vol. 122 Issue 1 Pg. 58-71 (Jul 2012) ISSN: 1471-4159 [Electronic] England
• PMID: 22533963 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Chemical References

• 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

Topics

• 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, metabolism)
• Oncogene Protein v-akt (metabolism)
• Oxotremorine (analogs & derivatives, pharmacology)
• Phosphorylation (drug effects)
• RNA, Small Interfering (metabolism)
• Signal Transduction (drug effects)
• Transfection