title: Interferon-β Inhibits Neurotrophin 3 Signalling and Pro-Survival Activity by Upregulating the Expression of Truncated TrkC-T1 Receptor.
abstract: Although clinically useful for the treatment of various diseases, type I interferons (IFNs) have been implicated as causative factors of a number of neuroinflammatory disorders characterized by neuronal damage and altered CNS functions. As neurotrophin 3 (NT3) plays a critical role in neuroprotection, we examined the effects of IFN-β on the signalling and functional activity of the NT3/TrkC system. We found that prolonged exposure of differentiated human SH-SY5Y neuroblastoma cells to IFN-β impaired the ability of NT3 to induce transphosphorylation of the full-length TrkC receptor (TrkC-FL) and the phosphorylation of downstream signalling molecules, including PLCγ1, Akt, GSK-3β and ERK1/2. NT3 was effective in protecting the cells against apoptosis triggered by serum withdrawal or thapsigargin but not IFN-β. Prolonged exposure to the cytokine had little effects on TrkC-FL levels but markedly enhanced the messenger RNA (mRNA) and protein levels of the truncated isoform TrkC-T1, a dominant-negative receptor that inhibits TrkC-FL activity. Cell depletion of TrkC-T1 by small interfering RNA (siRNA) treatment enhanced NT3 signalling through TrkC-FL and allowed the neurotrophin to counteract IFN-β-induced apoptosis. Furthermore, the upregulation of TrkC-T1 by IFN-β was associated with the inhibition of NT3-induced recruitment of the scaffold protein tamalin to TrkC-T1 and tamalin tyrosine phosphorylation. These data indicate that IFN-β exerts a negative control on NT3 pro-survival signalling through a novel mechanism involving the upregulation of TrkC-T1.
authors.affiliation: Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Dedoni
authors.affiliation: Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Olianas
authors.affiliation: Section of Applied Microbiology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Ingianni
authors.affiliation: Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy. onali@unica.it.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Onali
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D051379:Mice; D020933:Neurotrophin 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D020812:Receptor, trkC / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D020933:Neurotrophin 3; D016899:Interferon-beta; D020812:Receptor, trkC
keywords: Apoptosis; Human neuroblastoma cells; Interferon-β; Neurotrophin 3; Tamalin; TrkC