Imaizumi Tadaatsu, Yoshida Hidemi, Hayakari Ryo, Xing Fei, Wang Lian, Matsumiya Tomoh, Tanji Kunikazu, Kawaguchi Shogo, Murakami Manabu, Tanaka Hiroshi
Department of Vascular Biology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
Department of Vascular Biology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
Neurosci Res. 2016 Apr;105:35-41. doi: 10.1016/j.neures.2015.09.002. Epub 2015 Sep 28.
Treatment of cells with interferons (IFNs) induces the phosphorylation of signal transducer and activator of transcription 1 (STAT1), leading to the expression of hundreds of IFN-stimulated genes (ISGs). ISGs exert various antiviral and pro-inflammatory reactions. We have previously reported that ISG56 and ISG54 are induced by polyinosinic-polycytidylic acid (poly IC), an authentic agonist for Toll-like receptor 3 (TLR3), in U373MG human astrocytoma cells. ISG56 and ISG54 are also named as IFN-induced proteins with tetratricopeptide repeats (IFIT) 1 and IFIT2, respectively. In the present study, we demonstrated that poly IC induces the expression of ISG60, also named as IFIT3, in U373MG cells. RNA interference experiments showed that the induction of ISG60 by poly IC was mediated by TLR3, IFN-β, ISG56 and ISG54, whereas ISG60 is involved in poly IC-induced expression of ISG56, ISG54 and a chemokine CXCL10. The level of phosphorylated STAT1 was enhanced by poly IC, and it was inhibited by knockdown of ISG56, ISG54 or ISG60. These results suggest that there is a positive feedback loop between phosphorylated STAT1 and these ISGs.
用干扰素（IFN）处理细胞会诱导信号转导和转录激活因子1（STAT1）的磷酸化，从而导致数百种干扰素刺激基因（ISG）的表达。ISG发挥各种抗病毒和促炎反应。我们之前报道过，在U373MG人星形细胞瘤细胞中，Toll样受体3（TLR3）的真正激动剂多聚肌苷酸-多聚胞苷酸（poly IC）可诱导ISG56和ISG54的表达。ISG56和ISG54也分别被命名为含四肽重复序列的干扰素诱导蛋白（IFIT）1和IFIT2。在本研究中，我们证明了poly IC可在U373MG细胞中诱导ISG60（也称为IFIT3）的表达。RNA干扰实验表明，poly IC对ISG60的诱导是由TLR3、IFN-β、ISG56和ISG54介导的，而ISG60参与了poly IC诱导的ISG56、ISG54和趋化因子CXCL10的表达。poly IC可增强磷酸化STAT1的水平，而敲低ISG56、ISG54或ISG60可抑制该水平。这些结果表明，磷酸化STAT1与这些ISG之间存在正反馈回路。
