Resistance to IFN-alpha-induced apoptosis is linked to a loss of STAT2.
Resistance to IFN-alpha-induced apoptosis is linked to a loss of STAT2.
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DOI：
10.1158/1541-7786.mcr-08-0344
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发表时间：
2010-01
期刊：
影响因子：
--
通讯作者：
Gamero AM
中科院分区：
文献类型：
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作者：
Romero-Weaver AL;Wang HW;Steen HC;Scarzello AJ;Hall VL;Sheikh F;Donnelly RP;Gamero AM
Type I interferons (IFN-α/β) are pleitropic cytokines widely used in the treatment of certain malignancies, hepatitis B and C and multiple sclerosis. IFN resistance is a challenging clinical problem to overcome. Hence understanding the molecular mechanism by which IFN immunotherapy ceases to be effective is of translational importance. In this study, we report that continuous IFN-α stimulation of the human Jurkat variant H123 led to resistance to type I IFN-induced apoptosis due to a loss of STAT2 expression. The apoptotic effects of IFN-α were hampered as STAT2 deficient cells were defective in activating the mitochondrial-dependent death pathway and ISGF3-mediated gene activation. Reconstitution of STAT2 restored the apoptotic effects of IFN-α as measured by loss of mitochondrial membrane potential, cytochrome c release from mitochondria, caspase activation, and ultimately cell death. Nuclear localization of STAT2 was a critical event as retention of tyrosine phosphorylated STAT2 in the cytosol was not sufficient to activate apoptosis. Furthermore, silencing STAT2 gene expression in Saos2 and A375S.2 tumor cell lines significantly reduced the apoptotic capacity of IFN-α. Altogether we demonstrate that STAT2 is a critical mediator in the activation of type I IFN-induced apoptosis. More importantly, defects in the expression or nuclear localization of STAT2 could lessen the efficacy of type I IFN immunotherapy.
