Type I interferons up-regulate the expression and signalling of p75 NTR/TrkA receptor complex in differentiated human...

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.