Action mechanisms of Idarubicin as an Inducer for Interferon Signaling

• Main Authors: Pei-Jung Wu, 吳佩蓉
• Other Authors: Szu-Hao Kung
• Format: Others
• Language: zh-TW
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/18305750440156916507

碩士 === 國立陽明大學 === 醫學生物技術暨檢驗學系 === 103 === Enterovirus 71 (EV71) belongs to enterovirus genus in the family of Picornaviridae. EV71 infection causes hand-foot-mouth disease and neurological diseases in young children. The type I interferon (IFN) signaling is most important for innate antiviral responses. However, enteroviruses have evolved to counteract the IFN responses; this is exemplified by the findings that EV71 inhibits TLR3 and RIG-I signaling to restrict type I IFN production and reduces the level of IFN receptor to block IFN signaling. Our previous study showed that Idarubicin (IDR) displays anti-EV71 activities in sub-cytotoxic concentrations. Moreover, IDR has recently been reported to increase IFN stimulating response element (ISRE) activity at points after IFN receptor binding. However, the molecular mechanism of IDR underlying the IFN signal induction and antiviral effects remains to be explored. In this study, we showed that IDR promoted IFN signaling in the context of EV71 infection. Moreover, we found that IDR raised the protein level of interferon regulatory factor 9 (IRF9) but no significant activations in other components in the JAK-STAT pathway including Janus kinase 1 (JAK1)、Tyrosine kinase 2 (TYK2) and signal transducer and activator of transcription 1/2 (STAT1/2) as analyzed by a Western blot. In addition, knockdown of interferon regulatory factor 9 (IRF9) upon IDR treatment resulted in a significant increase in the viral yield and a decrease in ISRE activity, whereas knockdown of the upstream STAT1 or STAT2 did not. Furthermore, IDR treatment resulted in IRF9 translocation from the cytoplasm to the nucleus. Finally, among many ISGs detected in EV71-infected cells, we found that IDR selectively upregulated the OAS2 expression, which could directly implicated in the antiviral activity. In sum, we have attempted to elaborate the molecular mechanisms underlying the IFN signal-inducing activation by IDR in the context of EV71 infection. This finding could lead to develop a broad-spectrum antiviral drug based on IFN signal stimulation.