IFN-alpha induces transcription of hypoxia-inducible factor-1alpha to inhibit proliferation of human endothelial cells.
IFN-alpha induces transcription of hypoxia-inducible factor-1alpha to inhibit proliferation of human endothelial cells.
复制标题
DOI：
10.4049/jimmunol.181.2.1052
复制
发表时间：
2008-07-15
期刊：
影响因子：
--
通讯作者：
Pober JS
中科院分区：
文献类型：
--
作者：
Gerber SA;Pober JS
低氧诱导因子（HIF）-1α是一种转录因子亚基，在低氧条件下通过稳定蛋白质而增加，在常氧条件下IFN-α可增加人内皮细胞（ECs）中HIF-1 α的表达。IFN-α在2 h内使HIF-1α转录水平增加高达50%，并使HIF-1α蛋白表达加倍。基于药理学抑制研究，HIF-1α mRNA的增加涉及新的转录，不依赖于新的蛋白质合成，并且需要JAK信号。通过小干扰RNA的蛋白质敲低证实了JAK 1和TYK 2以及IFN刺激的基因因子3（ISGF 3）的参与。IFN-γ不显著诱导HIF-1α mRNA的表达，但增加了IFN-α作用的幅度和持续时间。IFN-α诱导的HIF-1α蛋白移位到细胞核，并可与DNA中的缺氧反应元件结合。然而，由于HIF-1α蛋白水平的增加不足，IFN-α处理未能诱导几种原型HIF应答基因（VEGF-A、PPARγ和前列环素合酶）的转录。尽管某些其他HIF应答基因（PHD 3和VEGF-C）在IFN-α和/或IFN-γ处理后被诱导，但这些应答不被HIF-1α的siRNA敲低抑制。此外，IFN-α对参与先天免疫的ISGF 3依赖性基因（viperin、OAS 2和CXCL 10）的诱导也不受HIF-1α敲低的影响。有趣的是，HIF-1α的敲低显著降低了IFN-α抑制内皮细胞增殖的能力。我们的结论是，IFN-α诱导HIF-1α在人内皮细胞的转录，通过JAK-ISGF 3途径在常氧条件下，这种反应有助于这种细胞因子的抗增殖活性。
Expression of hypoxia-inducible factor (HIF)-1α, a transcription factor subunit increased by protein stabilization in response to hypoxia, is increased in human endothelial cells (ECs) by IFN-α under normoxic conditions. IFN-α increases HIF-1α transcript levels within 2 h by up to 50% and doubles HIF-1α protein expression. Based on pharmacological inhibition studies, the increase in HIF-1α mRNA involves new transcription, is independent of new protein synthesis, and requires JAK signaling. Protein knockdown by small interfering RNA confirms the involvement of JAK1 and TYK2, as well of IFN-stimulated gene factor 3 (ISGF3). IFN-γ does not significantly induce HIF-1α mRNA, but increases the magnitude and duration of the IFN-α effect. IFN-α-induced HIF-1α protein translocates to the nucleus and can bind to hypoxia response elements in DNA. However, IFN-α treatment fails to induce transcription of several prototypic HIF-responsive genes (VEGF-A, PPARγ, and prostacyclin synthase) due to an insufficient increase in HIF-1α protein levels. Although certain other HIF-responsive genes (PHD3 and VEGF-C) are induced following IFN-α and/or IFN-γ treatment, these responses are not inhibited by siRNA knockdown of HIF-1α. Additionally, IFN-α induction of ISGF3-dependent genes involved in innate immunity (viperin, OAS2, and CXCL10) are also unaffected by knockdown of HIF-1α. Interestingly, knockdown of HIF-1α significantly reduces the capacity of IFN-α to inhibit endothelial cell proliferation. We conclude that IFN-α induces the transcription of HIF-1α in human endothelial cells though a JAK-ISGF3 pathway under normoxic conditions, and that this response contributes to the antiproliferative activity of this cytokine.
登录
查看更多内容
影响因子：
2.3
作者：
da Silva, AJ;Brickelmaier, M;Hochman, PS
通讯作者：
Hochman, PS
影响因子：
6.5
作者：
Clark, Paul R.;Manes, Thomas D.;Kluger, Martin S.
通讯作者：
Kluger, Martin S.
影响因子：
11.4
作者：
LEVY, DE;LEW, DJ;DARNELL, JE
通讯作者：
DARNELL, JE
影响因子：
4.4
作者：
Dengler, TJ;Pober, JS
通讯作者：
Pober, JS
影响因子：
11.2
作者：
Kondo, Satoru;Seo, So Young;Pagano, Joseph S.
通讯作者：
Pagano, Joseph S.