Interferon-β induces apoptosis in human SH-SY5Y neuroblastoma cells through activation of JAK-STAT signaling and down-regulation of PI3K/Akt pathway
Interferon-β induces apoptosis in human SH-SY5Y neuroblastoma cells through activation of JAK-STAT signaling and down-regulation of PI3K/Akt pathway
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DOI：
10.1111/j.1471-4159.2010.07046.x
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发表时间：
2010-12-01
影响因子：
4.7
通讯作者：
Onali, Pierluigi
中科院分区：
文献类型：
--
作者：
Dedoni, Simona;Olianas, Maria C.;Onali, Pierluigi
I型干扰素（IFN）是已知的引起神经精神副作用，这已被提出是由外周活动或激活胶质细胞介导。在本研究中，我们已经调查了这些细胞因子是否可以直接作用于神经细胞和调节参与细胞死亡的信号通路。在人SH-SY 5 Y神经母细胞瘤细胞中，I型IFN通过I型IFN受体迅速刺激Janus激酶和信号转导和转录激活因子（STAT）的酪氨酸磷酸化。长期暴露于IFN-β诱导凋亡性细胞死亡，伴随细胞色素C释放，半胱天冬酶9，7，3和聚-（ADP核糖）聚合酶和DNA片段化的切割。Janus激酶抑制降低了IFN-β刺激的TyK 2和STAT 1磷酸化、STAT 1转录活性、双链RNA活化蛋白激酶（PKR）的诱导和半胱天冬酶切割。PKR诱导与增强的PKR活性和PKR的化学抑制减少IFN刺激的半胱天冬酶活化相关。此外，长期IFN-β治疗导致磷脂酰肌醇3-激酶/Akt信号转导的下调，并且IFN-β诱导的细胞凋亡在表达组成性活性Akt的细胞中减弱。类似地，在小鼠原代神经元中，IFN-β诱导STAT磷酸化、半胱天冬酶3裂解和Akt信号传导的抑制。因此，I型干扰素可以通过调节促进内在凋亡途径的多种信号分子直接损害神经元存活。这种效应可能有助于细胞因子的神经毒性。
P>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-beta 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-beta-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-beta treatment led to down-regulation of phosphatidylinositol 3-kinase/Akt signaling and IFN-beta-induced apoptosis was attenuated in cells expressing constitutively active Akt. Similarly, in mouse primary neurons IFN-beta 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.