Yim J H, Wu S J, Lowney J K, Vander Velde T L, Doherty G M
Cytokine and Tumor Biology Laboratory, Department of Surgery, Washington School of Medicine, St. Louis, MO 63110-1093, USA.
J Interferon Cytokine Res. 1999 Jul;19(7):723-9. doi: 10.1089/107999099313569.
We investigated the role of interferon (IFN) regulatory factor-2 (IRF-2) as an oncoprotein in vivo, opposing endogenous IFN-gamma suppression of tumor growth. Using syngeneic IFN-gamma knockout mice, we show that endogenous IFN-gamma slows growth of the mouse melanoma cell line B16-F10 in immunocompetent mice, suggesting that tumor cell resistance to IFN-gamma may lead to greater tumorigenicity. IRF-2 is a nuclear transcription factor induced by IFN-gamma that represses numerous IFN-inducible genes, including genes that regulate cell growth, in opposition to the transcriptional activator IRF-1. B16-F10 has a marked growth inhibitory response to IFN-gamma in vitro and has very little IRF-2 induction compared with other murine tumor cell lines. We engineered B16-F10 cells to stably overexpress murine IRF-2. In vitro, these transfected cells showed a marked resistance to the growth-inhibitory effect of IFN-gamma. In normal mice the IRF-2-transfected cells grew much faster than control tumors. In syngeneic IFN-gamma knockout mice, control cells grew at a rate similar to that of IRF-2-transfected cells, implicating resistance to endogenous IFN-gamma as playing the major role in enhanced growth of IRF-2-transfected tumors in intact mice. These experiments demonstrate that (1) IRF-2 enhances B16 melanoma growth and increases resistance to IFN-gamma in vitro, and (2) IRF-2 opposes the growth suppression mediated by endogenous IFN-gamma in vivo.
我们研究了干扰素（IFN）调节因子2（IRF-2）作为一种癌蛋白在体内的作用，它可对抗内源性IFN-γ对肿瘤生长的抑制。利用同基因IFN-γ基因敲除小鼠，我们发现内源性IFN-γ可减缓免疫活性小鼠体内黑色素瘤细胞系B16-F10的生长，这表明肿瘤细胞对IFN-γ的抗性可能导致更高的致瘤性。IRF-2是一种由IFN-γ诱导的核转录因子，它可抑制众多IFN诱导基因，包括调控细胞生长的基因，这与转录激活因子IRF-1相反。B16-F10在体外对IFN-γ有明显的生长抑制反应，与其他小鼠肿瘤细胞系相比，其IRF-2的诱导水平非常低。我们构建了稳定过表达小鼠IRF-2的B16-F10细胞。在体外，这些转染细胞对IFN-γ的生长抑制作用表现出明显抗性。在正常小鼠中，转染IRF-2的细胞比对照肿瘤生长快得多。在同基因IFN-γ基因敲除小鼠中，对照细胞的生长速度与转染IRF-2的细胞相似，这表明对内源性IFN-γ的抗性在完整小鼠中IRF-2转染肿瘤的生长增强中起主要作用。这些实验证明：（1）IRF-2在体外增强B16黑色素瘤的生长并增加对IFN-γ的抗性；（2）IRF-2在体内对抗内源性IFN-γ介导的生长抑制。
