|Titolo:||Type I interferons induce apoptosis in human neuroblastoma cells: Modulation by glycogen synthase kinase-3β activity|
|Data di pubblicazione:||2009|
|Abstract:||The clinical use of interferon-α (IFN-α) and interferon-β (IFN-β) has been associated with the occurrence of neuropsychiatric side effects, including cognitive, emotional and mood disturbances, through still undefined mechanisms. In the present study we have used the neuroblastoma cell line SH-SY5Y to investigate the effects of IFNs on a human neural cell model. We found that in these cells human IFN-α and IFN-β markedly stimulated STAT1 phosphorylation at Tyr701 with picomolar potencies. The stimulation of STAT1 phosphorylation by IFNs was antagonized in a concentration-dependent manner by a neutralizing antibody directed against the IFN receptor protein, indicating the presence of functional IFN receptors. Long-term ( 24 h) cell exposure to IFNs caused cell death associated with activation of caspase-9 and -3, poly (ADP ribose) polymerase (PARP) cleavage and DNA fragmentation, indicating the occurrence of apoptosis. These effects were accompanied by enhanced protein kinase R expression and phosphorylation of the translation initiation factor eIF2α. Cell pretreatment with the glycogen synthase kinase-3β (GSK-3β) inhibitor SB 216763 significantly reduced IFN-induced caspase activation, PARP cleavage and DNA fragmentation. These data indicate that type I IFNs can act directly on human neural cells to induce apoptosis and that this toxic effect can be attenuated by inhibition of GSK-3β activity|
File in questo prodotto:
Non ci sono file associati a questo prodotto.