Yim John H, Ro Simon H, Lowney Jennifer K, Wu Susan J, Connett Judith, Doherty Gerard M
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
J Interferon Cytokine Res. 2003 Sep;23(9):501-11. doi: 10.1089/10799900360708623.
Interferon (IFN) regulatory factor-1 (IRF-1) and IRF-2 play opposing roles in the regulation of many IFN-gamma-inducible genes. To investigate the signal transduction pathway in response to IFN-gamma in light of differences in growth effects, we selected four human breast carcinoma cell lines based on a spectrum of growth inhibition by IFN-gamma. MDA468 growth was markedly inhibited by IFN-gamma, and it showed substantial induction of IRF-1 mRNA but little IRF-2 induction. SKBR3 showed little growth inhibition and little induction of IRF-1 mRNA but significant induction of IRF-2 mRNA. HS578T and MDA436 growth inhibition and IRF-1/IRF-2 induction were intermediate. All four cell lines showed intact receptor at the cell surface and Stat1 translocation to the nucleus by immunostaining. By EMSA, there were marked differences in the induced ratio of IRF-1 and IRF-2 binding activity between the cell lines that correlated with growth inhibition. Finally, antisense oligonucleotides specific for IRF-1 attenuated IFN-gamma growth inhibition in MDA436 and MDA468, confirming the direct role of IRF-1 in IFN-gamma growth inhibition. Induction of IRF-1 causes growth inhibition in human breast cancer cell lines, and induction of IRF-2 can oppose this. The relative induction of IRF-1 to IRF-2 is a critical control point in IFN-gamma response.
干扰素（IFN）调节因子-1（IRF-1）和IRF-2在许多γ干扰素诱导基因的调控中发挥着相反的作用。为了根据生长效应的差异研究对γ干扰素的信号转导途径，我们基于γ干扰素对生长抑制的一系列情况选择了四种人乳腺癌细胞系。MDA468的生长受到γ干扰素的显著抑制，它显示出IRF-1 mRNA的大量诱导但IRF-2诱导很少。SKBR3几乎没有生长抑制，IRF-1 mRNA诱导很少但IRF-2 mRNA有显著诱导。HS578T和MDA436的生长抑制以及IRF-1/IRF-2诱导处于中间水平。通过免疫染色，所有四种细胞系在细胞表面均显示完整的受体以及Stat1易位至细胞核。通过电泳迁移率变动分析（EMSA），细胞系之间IRF-1和IRF-2结合活性的诱导比例存在显著差异，这与生长抑制相关。最后，针对IRF-1的反义寡核苷酸减弱了MDA436和MDA468中γ干扰素的生长抑制，证实了IRF-1在γ干扰素生长抑制中的直接作用。IRF-1的诱导导致人乳腺癌细胞系生长抑制，而IRF-2的诱导可对此起到拮抗作用。IRF-1与IRF-2的相对诱导是γ干扰素反应中的一个关键控制点。
