Mechanism of activation of interferon-stimulated genes by HTLV-1 Tax

采用RT-PCR差异显示技术研究HTLV-1诱导Tax转化的大鼠-1成纤维细胞的基因表达。分析结果显示，在tax -转化细胞中，8个基因表达上调，1个基因表达抑制。6例上调依赖于NF-kB途径，有趣的是，其中至少4例是干扰素刺激基因（ISGs）。2’-5’寡核苷酸合成酶（2-5’oligoadenylate synthetase, 2-5’OAS）基因在Tax-转化的大鼠1细胞和原代ATL细胞中都被激活，对该基因的启动子分析表明，Tax和NF-kB都激活了其干扰素响应增强元件。此外，NF-kB分子的显性活性形式抑制了这种激活。虽然在Tax转化的大鼠1细胞和原代ATL细胞中观察到干扰素b基因的表达，但加入抗干扰素a和b的抗体并不能消除Tax对ISRE报告基因的激活。因此，这表明，税收间接激活ISRE，可能是通过诱导一些ISRE结合蛋白，如干扰素反应因子，irf的成员。在tax -转化的细胞中，未观察到IRF-1、-3和-7的表达增强，但IRF-2和IRF-4在表达载体激活ISRE报告质粒时过表达，而IRF-2和IRF-4最初被鉴定为抑制因子。由于有报道称IRF-4在HTLV-1转化的t细胞中高表达，并通过rel癌基因参与鸡成纤维细胞的细胞转化，因此有人认为IRF-4参与了税收介导的大鼠-1细胞的转化。

Gene expression in Rat-1 fibroblast cells transformed by Tax from HTLV-1 was studied using the RT-PCR differential display technique. The analysis revealed that eight genes were upregulated and one gene was suppressed in Tax-transformed cells. Six cases of upregulation were dependent on the NF-kB pathway and, interestingly, at least four of them were interferon-stimulated genes (ISGs). Promoter analysis of the 2'-5' oligoadenylate synthetase (2-5 OAS) gene, which was activated in both Tax-transformed Rat-1 cells and primary ATL cells, demonstrated that both Tax and NF-kB activate its interferon-responsive enhancer element. Furthermore, dominant active form of the NF-kB molecule suppressed the activation. Although the expression of interferon b gene was observed in Tax-transformed rat1 cells and primary ATL cells, addition of antibodies against interferon a and b did not abrogate the activation of ISRE reporter by Tax. It was thus indicated that Tax activates the ISRE indirectly, probably through induction of some ISRE binding proteins such as members of interferon responsive factors, IRFs.Enhanced expression of IRF-1, -3 and -7 was not observed in Tax-transformed cells but overexpression of IRF-2 and IRF-4, which were originally identified as repressors, with expression vectors activated the ISRE reporter plasmid. Since IRF-4 has been reported to be highly expressed in HTLV-1 transformed T-cells and to be involved in cellular transformation of chicken fibroblasts by rel oncogene, involvement of IRF-4 in Tax-mediated transformation of Rat-1 cells was suggested.