IRF9 is a key factor for eliciting the antiproliferative activity of IFN-alpha.
IRF9 is a key factor for eliciting the antiproliferative activity of IFN-alpha.
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DOI：
10.1097/cji.0b013e3181ad4092
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发表时间：
2009-10
期刊：
影响因子：
--
通讯作者：
Zoon KC
中科院分区：
文献类型：
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作者：
Tsuno T;Mejido J;Zhao T;Schmeisser H;Morrow A;Zoon KC
许多肿瘤仍然对人干扰素（IFN）-α的抗增殖活性具有抗性。Janus激酶/信号转导和转录激活因子（JAK-STAT）通路在初始IFN信号传导中起重要作用。为了增强IFN-α的抗增殖活性，重要的是阐明JAK-STAT通路中哪些因子在引发这种活性中起关键作用。在对IFN-α和IFN-γ均敏感的人卵巢腺癌OVCAR 3细胞中，只有IFN调节因子9（IRF 9）-RNA干扰（RNAi）完全抑制了细胞内JAK-STAT通路因子中IFN-α的抗增殖活性。相反，Stat 1-RNAi不抑制IFN-α的抗增殖活性，而部分抑制IFN-γ的抗增殖活性。作为细胞死亡途径，据报道肿瘤坏死因子相关凋亡诱导配体（TRAIL）通过TRAIL-R（受体）1和TRAIL-R2诱导细胞凋亡。在IFN-α处理的OVCAR 3细胞中，IRF 9-RNAi抑制了TRAIL的转录，而Stat 1-RNAi则没有，这表明IFN-α诱导的TRAIL转录主要需要IRF 9。此外，IFN-α处理后，TRAIL的IFN刺激的反应元件（ISRE）样基序与IFN刺激的基因因子3（ISGF 3）复合物结合。随后，TRAIL-R2-RNAi抑制IFN-α和TRAIL的抗增殖活性，表明TRAIL-R2介导IFN-α和TRAIL信号以引发其抗增殖活性。最后，IRF 9过表达促进了IFN-α诱导的T98 G（人多形性胶质母细胞瘤）细胞凋亡，该细胞对IFN-α具有抗性。因此，我们的研究表明，IRF 9是诱导IFN-α抗增殖活性的关键因子，TRAIL可能是潜在的介导因子之一。
A number of tumors are still resistant to the antiproliferative activity of human interferon (IFN)-α. The Janus kinases/Signal Transducers and Activators of Transcription (JAK-STAT) pathway plays an important role in initial IFN signaling. In order to enhance the antiproliferative activity of IFN-α, it is important to elucidate which factors in the JAK-STAT pathway play a key role in eliciting this activity. In human ovarian adenocarcinoma OVCAR3 cells sensitive to both IFN-α and -γ, only IFN regulatory factor 9 (IRF9)-RNA interference (RNAi) completely inhibited the antiproliferative activity of IFN-α among the intracellular JAK-STAT pathway factors. Conversely, Stat1-RNAi did not inhibit the antiproliferative activity of IFN-α, while it partially inhibited that of IFN-γ. As a cell death pathway, it is reported that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis via TRAIL-R (receptor) 1 and TRAIL-R2. In IFN-α-treated OVCAR3 cells, IRF9-RNAi inhibited transcription of TRAIL while Stat1-RNAi did not, suggesting that the transcription of TRAIL induced by IFN-α predominantly required IRF9. Furthermore, IFN-stimulated response element (ISRE)-like motifs of TRAIL bound to IFN-stimulated gene factor 3 (ISGF3) complex following IFN-α treatment. Subsequently, TRAIL-R2-RNAi inhibited both antiproliferative activities of IFN-α and TRAIL, suggesting that TRAIL-R2 mediated both IFN-α and TRAIL signals to elicit their antiproliferative activities. Finally, IRF9 overexpression facilitated IFN-α-induced apoptosis in T98G (human glioblastoma multiforme) cells, which were resistant to IFN-α. Thus, our present study suggests that IRF9 is the key factor for eliciting the antiproliferative activity of IFN-α and TRAIL may be one of the potential mediators.