Journal
JOURNAL OF NEUROCHEMISTRY
Volume 122, Issue 1, Pages 58-71Publisher
WILEY
DOI: 10.1111/j.1471-4159.2012.07766.x
Keywords
cell survival; differentiated neuroblastoma cells; mouse cortical neurons; neuritogenesis; TrkB signaling; type I interferons
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Funding
- MIUR [DM 28142]
- Regione Autonoma della Sardegna
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J. Neurochem. (2012) 122, 5871. 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 C? and extracellular-regulated kinases 1 and 2 signaling. Moreover, IFN-beta inhibited BDNF-induced cell survival, neurite outgrowth, and expression of neuronal markers, such as neurofilament proteins, growth-associated protein-43 and glutamate a-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-beta-induced TrkB down-regulation. Quantitative real time RT-PCR indicated that IFN-beta significantly reduced TrkB mRNA levels. Moreover, blockade of protein kinase R counteracted IFN-beta-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.
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