Identification of genes selectively regulated by IFNs in endothelial cells
Identification of genes selectively regulated by IFNs in endothelial cells
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DOI：
10.4049/jimmunol.178.2.1122
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发表时间：
2007-01-15
影响因子：
4.4
通讯作者：
Amadori, Alberto
中科院分区：
文献类型：
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作者：
Indraccolo, Stefano;Pfeffer, Ulrich;Amadori, Alberto
IFN是高度多效性的细胞因子，也具有显著的抗血管生成活性。在这项研究中，内皮细胞（EC）暴露于体外IFN-α，IFN-β，或IFN-γ的mRNA表达谱进行了测定。我们发现，在HUVEC以及其他EC类型中，175个基因被IFN上调（> 2倍增加），包括参与宿主对RNA病毒、炎症和凋亡反应的基因。有趣的是，与人成纤维细胞相比，41个基因在EC中显示出> 5倍的IFN-α诱导;其中，编码血管抑制趋化因子CXCL 11的基因在EC中被IFN-α选择性诱导，沿着与血管生成调节相关的其他基因，包括CXCL 10、TRAIL和鸟苷酸结合蛋白1。这些转录的变化得到证实，并通过定量PCR分析和ELISA延长;而IFN-α和IFN-β发挥几乎相同的作用，转录组调制，差异基因调控I型和II型IFN出现，特别是就定量方面而言。在体内，产生IFN-α的肿瘤过表达鼠CXCL 10和CXCL 11、鸟苷酸结合蛋白1和TRAIL，有证据表明肿瘤相关EC产生CXCL 11。总的来说，这些研究结果提高了我们的理解，干扰素的抗血管生成的影响，表明这些细胞因子触发EC的抗血管生成的转录程序。此外，我们认为，IFN-应答基因的转录激活的幅度的定量差异可以形成细胞特异性转录签名的基础。
IFNs are highly pleiotropic cytokines also endowed with marked antiangiogenic activity. In this study, the mRNA expression profiles of endothelial cells (EC) exposed in vitro to IFN-alpha, IFN-beta, or IFN-gamma were determined. We found that in HUVEC as well as in other EC types 175 genes were up-regulated (> 2-fold increase) by IFNs, including genes involved in the host response to RNA viruses, inflammation, and apoptosis. Interestingly, 41 genes showed a > 5-fold higher induction by IFN-alpha in EC compared with human fibroblasts; among them, the gene encoding the angiostatic chemokine CXCL11 was selectively induced by IFN-a in EC along with other genes associated with angiogenesis regulation, including CXCL1O, TRAIL, and guanylate-binding protein 1. These transcriptional changes were confirmed and extended by quantitative PCR analysis and ELISA; whereas IFN-alpha and IFN-beta exerted virtually identical effects on transcriptome modulation, a differential gene regulation by type I and type II IFN emerged, especially as far as quantitative aspects were concerned. In vivo, IFN-alpha-producing tumors overexpressed murine CXCL10 and CXCL11, guanylate-binding protein 1, and TRAIL, with evidence of CXCL11 production by tumor-associated EC. Overall, these findings improve our understanding of the antiangiogenic effects of IFNs by showing that these cytokines trigger an antiangiogenic transcriptional program in EC. Moreover, we suggest that quantitative differences in the magnitude of the transcriptional activation of IFN-responsive genes could form the basis for cell-specific transcriptional signatures.