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Type I interferons impair BDNF‐induced cell signaling and neurotrophic activity in differentiated human SH‐SY5Y neuroblastoma cells and mouse primary cortical neurons
Author(s) -
Dedoni Simona,
Olianas Maria C.,
Ingianni Angela,
Onali Pierluigi
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2012.07766.x
Subject(s) - tropomyosin receptor kinase b , microbiology and biotechnology , tropomyosin receptor kinase a , neurotrophic factors , signal transduction , biology , janus kinase , brain derived neurotrophic factor , sh sy5y , neurotrophin , stat protein , chemistry , cancer research , receptor , stat3 , neuroblastoma , biochemistry , cell culture , genetics
J. Neurochem. (2012) 122 , 58–71. 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.