PMID- 22533963 OWN - NLM STAT- MEDLINE DCOM- 20120827 LR - 20161125 IS - 1471-4159 (Electronic) IS - 0022-3042 (Linking) VI - 122 IP - 1 DP - 2012 Jul TI - Type I interferons impair BDNF-induced cell signaling and neurotrophic activity in differentiated human SH-SY5Y neuroblastoma cells and mouse primary cortical neurons. PG - 58-71 LID - 10.1111/j.1471-4159.2012.07766.x [doi] AB - 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 Cgamma 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 alpha-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. CI - (c) 2012 The Authors. Journal of Neurochemistry (c) 2012 International Society for Neurochemistry. FAU - Dedoni, Simona AU - Dedoni S AD - Department of Neuroscience, University of Cagliari, Cagliari, Italy. FAU - Olianas, Maria C AU - Olianas MC FAU - Ingianni, Angela AU - Ingianni A FAU - Onali, Pierluigi AU - Onali P LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120521 PL - England TA - J Neurochem JT - Journal of neurochemistry JID - 2985190R RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Interferon Type I) RN - 0 (Muscarinic Agonists) RN - 0 (RNA, Small Interfering) RN - 5RY0UWH1JL (Oxotremorine) RN - 63939-65-1 (oxotremorine M) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Oncogene Protein v-akt) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) SB - IM MH - Animals MH - Animals, Newborn MH - Brain-Derived Neurotrophic Factor/*pharmacology MH - Cell Differentiation/*drug effects MH - Cell Survival/drug effects MH - Cells, Cultured MH - Drug Interactions MH - Female MH - Frontal Lobe/*cytology MH - Gene Expression Regulation/drug effects MH - Glycogen Synthase Kinase 3/metabolism MH - Glycogen Synthase Kinase 3 beta MH - Humans MH - Interferon Type I/*pharmacology MH - Male MH - Mice MH - Muscarinic Agonists/pharmacology MH - Neuroblastoma/pathology MH - Neurogenesis/drug effects MH - Neurons/*drug effects/metabolism MH - Oncogene Protein v-akt/metabolism MH - Oxotremorine/analogs & derivatives/pharmacology MH - Phosphorylation/drug effects MH - RNA, Small Interfering/metabolism MH - Signal Transduction/*drug effects MH - Transfection EDAT- 2012/04/27 06:00 MHDA- 2012/08/28 06:00 CRDT- 2012/04/27 06:00 PHST- 2012/04/27 06:00 [entrez] PHST- 2012/04/27 06:00 [pubmed] PHST- 2012/08/28 06:00 [medline] AID - 10.1111/j.1471-4159.2012.07766.x [doi] PST - ppublish SO - J Neurochem. 2012 Jul;122(1):58-71. doi: 10.1111/j.1471-4159.2012.07766.x. Epub 2012 May 21.