title: Type I interferons up-regulate the expression and signalling of p75 NTR/TrkA receptor complex in differentiated human SH-SY5Y neuroblastoma cells.
abstract: Both type I interferons (IFNs) and neurotrophins regulate neuroadaptive responses, but relatively little is known on the interaction between these two classes of regulatory proteins. Here we investigated the effect of IFN-β on the expression and functional activity of the common neurotrophin receptor p75NTR and the nerve growth factor (NGF) receptor TrkA. In differentiated human SH-SY5Y neuroblastoma cells prolonged exposure to IFN-β up-regulated p75NTR and TrkA levels, failed to affect the content of sortilin, a p75NTR co-receptor, and, consistent with our previous finding, down-regulated the brain-derived neurotrophic factor receptor TrkB. Quantitative real time RT-PCR indicated that IFN-β increased p75NTR and TrkA mRNA levels. In control and IFN-β treated cells proNGF failed to induce c-Jun N-terminal kinase and nuclear factor/kB activation, two p75NTR/sortilin signalling pathways mediating neuronal death. On the other hand, IFN-β treatment enhanced TrkA autophosphorylation and signalling induced by NGF and proNGF. Knockdown of p75NTR by siRNA reduced TrkA activation by proNGF and a subnanomolar concentration of NGF, whereas co-immunoprecipitation indicated close association of p75NTR and TrkA. Co-treatment with either NGF or proNGF reduced IFN-β pro-apoptotic and anti-neurotrophic effects. Similarly, in primary mouse hippocampal neurons IFN-β increased p75NTR and TrkA expression, down-regulated TrkB and enhanced NGF-induced phosphorylation of the pro-survival protein kinase Akt. The data demonstrate that in neuronal cells IFN-β differentially affects the expression and signalling of neurotrophin receptors and suggest that the up-regulation of the p75NTR/TrkA signalling complex may constitute a novel mechanism by which this cytokine selectively attenuates its pro-apoptotic effect in NGF-responsive cells.
authors: Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences and Clinical Pharmacology, and Section of Applied Microbiology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors: Simona
authors: S
authors: Dedoni
authors: Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences and Clinical Pharmacology, and Section of Applied Microbiology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors: Maria C
authors: MC
authors: Olianas
authors: Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences and Clinical Pharmacology, and Section of Applied Microbiology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors: Angela
authors: A
authors: Ingianni
authors: Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences and Clinical Pharmacology, and Section of Applied Microbiology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy. Electronic address: onali@unica.it.
authors: Pierluigi
authors: P
authors: Onali
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D020932:Nerve Growth Factor / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016899:Interferon-beta; D020932:Nerve Growth Factor; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor; D000099183:Sortilin; C484065:NGFR protein, human; C517634:Ngfr protein, mouse
keywords: Neuronal apoptosis; Neurotrophins; Signal transduction; TrkA; Type I interferons; p75NTR