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

被引:32
作者
Dedoni, Simona [1 ]
Olianas, Maria C. [1 ]
Ingianni, Angela [2 ]
Onali, Pierluigi [1 ]
机构
[1] Univ Cagliari, Dept Neurosci, Cagliari, Italy
[2] Univ Cagliari, Dept Biomed Sci, Cagliari, Italy
关键词
cell survival; differentiated neuroblastoma cells; mouse cortical neurons; neuritogenesis; TrkB signaling; type I interferons; PROTEIN-KINASE; MEDIATED SURVIVAL; RETINOIC ACID; ALPHA; INDUCTION; TRKB; EXPRESSION; MECHANISM; PTEN; BETA;
D O I
10.1111/j.1471-4159.2012.07766.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:58 / 71
页数:14
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