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

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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.