Interferon regulatory factor 1 (IRF-1) and IRF-2 distinctively up-regulate gene expression and production of interleukin-7 in human intestinal epithelial cells
Interferon regulatory factor 1 (IRF-1) and IRF-2 distinctively up-regulate gene expression and production of interleukin-7 in human intestinal epithelial cells
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DOI：
10.1128/mcb.24.14.6298-6310.2004
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发表时间：
2004-07-01
影响因子：
5.3
通讯作者：
Watanabe, M
中科院分区：
文献类型：
--
作者：
Oshima, S;Nakamura, T;Watanabe, M
肠上皮细胞来源的白细胞介素（IL）-7在人肠粘膜中作为多效性和非冗余的细胞因子发挥作用;然而，其产生的分子基础仍然完全未知。我们在这里表明，人肠上皮细胞组成性和γ干扰素（IFN-γ）诱导产生IL-7，而我们测试的其他几个因素没有影响。通过IFN调节因子元件（IRF-E）在5'侧翼区上的转录调节（其缺乏典型核心启动子序列）对于IL-7表达的两种模式都是关键的。IRF-1和IRF-2（后者通常被称为转录阻遏物）显示分别以IFN-γ诱导型和组成型方式与IRF-E相互作用并反式激活IL-7基因表达。事实上，四环素诱导的表达实验表明，这两种IRF蛋白上调IL-7蛋白的产生，其独特的作用进一步证实了小干扰RNA介导的基因沉默系统。此外，这些IRFs显示出关于IL-7转录物在人结肠上皮组织内活化和表达模式的特征。这些结果表明，IRF-1和IRF-2之间的功能相互作用作为一个精心设计的和合作的机制，及时以及连续的调节IL-7的生产，是必不可少的局部免疫调节人体肠粘膜内。
Intestinal epithelial cell-derived interleukin (IL)-7 functions as a pleiotropic and nonredundant cytokine in the human intestinal mucosa; however, the molecular basis of its production has remained totally unknown. We here showed that human intestinal epithelial cells both constitutively and when induced by gamma interferon (IFN-gamma) produced IL-7, while several other factors we tested had no effect. Transcriptional regulation via an IFN regulatory factor element (IRF-E) on the 5' flanking region, which lacks canonical core promoter sequences, was pivotal for both modes of IL-7 expression. IRF-1 and IRF-2, the latter of which is generally known as a transcriptional repressor, were shown to interact with IRF-E and transactivate IL-7 gene expression in an IFN-gamma-inducible and constitutive manner, respectively. Indeed, tetracycline-inducible expression experiments revealed that both of these IRF proteins up-regulated IL-7 protein production, and their exclusive roles were further confirmed by small interfering RNA-mediated gene silencing systems. Moreover, these IRFs displayed distinct properties concerning the profile of IL-7 transcripts upon activation and expression patterns within human colonic epithelial tissues. These results suggest that the functional interplay between IRF-1 and IRF-2 serves as an elaborate and cooperative mechanism for timely as well as continuous regulation of IL-7 production that is essential for local immune regulation within human intestinal mucosa.