Bandarra Daniel, Biddlestone John, Mudie Sharon, Müller H-Arno J, Rocha Sonia
Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dow Street, DD1 5EH, UK.
Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dow Street, DD1 5EH, UK.
Dis Model Mech. 2015 Feb;8(2):169-81. doi: 10.1242/dmm.017285. Epub 2014 Dec 15.
Hypoxia and inflammation are intimately linked. It is known that nuclear factor κB (NF-κB) regulates the hypoxia-inducible factor (HIF) system, but little is known about how HIF regulates NF-κB. Here, we show that HIF-1α represses NF-κB-dependent gene expression. HIF-1α depletion results in increased NF-κB transcriptional activity both in mammalian cells and in the model organism Drosophila melanogaster. HIF-1α depletion enhances the NF-κB response, and this required not only the TAK-IKK complex, but also CDK6. Loss of HIF-1α results in an increased angiogenic response in mammalian cancer cells and increased mortality in Drosophila following infection. These results indicate that HIF-1α is required to restrain the NF-κB response, and thus prevents excessive and damaging pro-inflammatory responses.
缺氧与炎症密切相关。已知核因子κB（NF-κB）调节缺氧诱导因子（HIF）系统，但关于HIF如何调节NF-κB却知之甚少。在此，我们表明HIF-1α抑制NF-κB依赖性基因表达。在哺乳动物细胞和模式生物黑腹果蝇中，HIF-1α的缺失都会导致NF-κB转录活性增加。HIF-1α的缺失增强了NF-κB反应，这不仅需要TAK-IKK复合物，还需要CDK6。HIF-1α的缺失导致哺乳动物癌细胞中血管生成反应增加，以及果蝇感染后死亡率增加。这些结果表明，HIF-1α是抑制NF-κB反应所必需的，从而防止过度和有害的促炎反应。
