Interferon-β induces apoptosis in human SH-SY5Y neuroblastoma cells through activation of JAK-STAT signaling and down-regulation of PI3K/Akt pathway.
Type I interferons (IFNs) are known to cause neuropsychiatric side effects, which have been proposed to be mediated by either peripheral actions or activation of glial cells. In the present study, we have investigated whether these cytokines could act directly on neuronal cells and regulate signaling pathways involved in cell death. In human SH-SY5Y neuroblastoma cells, type I IFNs rapidly stimulated tyrosine phosphorylation of Janus kinase and signal transducer and activator of transcription (STAT) through type I IFN receptor. Prolonged exposure to IFN-β induced apoptotic cell death accompanied by cytochrome C release, cleavage of caspases 9, 7, 3 and poly-(ADP ribose) polymerase and DNA fragmentation. Janus kinase inhibition reduced IFN-β-stimulated TyK2 and STAT1 phosphorylation, STAT1 transcriptional activity, induction of double-stranded RNA-activated protein kinase (PKR) and caspase cleavage. PKR induction was associated with enhanced PKR activity and chemical inhibition of PKR reduced IFN-stimulated caspase activation. Moreover, long-term IFN-β treatment led to down-regulation of phosphatidylinositol 3-kinase/Akt signaling and IFN-β-induced apoptosis was attenuated in cells expressing constitutively active Akt. Similarly, in mouse primary neurons IFN-β induced STAT phosphorylation, caspase 3 cleavage and inhibition of Akt signaling. Thus, type I IFNs can directly impair neuronal survival by regulating multiple signaling molecules promoting the intrinsic apoptotic pathway. This effect may contribute to the cytokine neurotoxicity.
Department of Neuroscience, Section of Biochemical Pharmacology, University of Cagliari, Cagliari, Italy.
Simona
S
Dedoni
Maria C
MC
Olianas
Pierluigi
P
Onali
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000502:physiology*; D006801:Humans; D016899:Interferon-beta / Q000502:physiology*; D053612:Janus Kinases / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D009447:Neuroblastoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D000081082:Phosphoinositide-3 Kinase Inhibitors; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D016899:Interferon-beta; D058539:Phosphatidylinositol 3-Kinase; D053612:Janus Kinases; D051057:Proto-Oncogene Proteins c-akt