NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α
NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α
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DOI：
10.1038/nature06905
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发表时间：
2008-06-05
期刊：
影响因子：
64.8
通讯作者：
Karin, Michael
中科院分区：
文献类型：
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作者：
Rius, Jordi;Guma, Monica;Karin, Michael
低氧反应是一种古老的由低氧(O(2))引发的应激反应。1)，并受低氧诱导转录因子-1(HIF-1)控制，HIF-1的α亚基在常氧条件下迅速降解，但当针对其O(2)依赖降解区的依赖O(2)的Pro羟基酶(PhDS)被抑制时稳定(2-4)。因此，控制能量代谢和血管生成相关基因的HIF-1α的数量在翻译后受到调节。另一种古老的应激反应是先天免疫反应，由几种转录因子调节，其中核因子-kappa B发挥核心作用(5，6)。核因子-kappaB的激活是由ikappa B激酶(IKK)控制的，主要是iKappaB-β，在感染和炎症反应中通过磷酸化诱导ikappa B抑制物的降解(7)。当抑制IKK-β活性的PhD被抑制时，IKK-β在低氧细胞培养中被适度激活(8)。然而，确定核因子-kappaB和HIF-1α之间的关系已被证明是难以捉摸的。在体外系统中，报道了HIF-1α激活核因子-kappaB(9)，核因子-kappa B控制HIF-1α转录(10)，HIF-1α激活可能同时抑制核因子-kappa B(11)。在这里，我们通过在不同细胞类型中缺乏IKK-β的小鼠的使用表明，核因子-kappa B是HIF-1α的关键转录激活因子，并且在低氧条件下培养细胞以及低氧动物的肝脏和脑中的HIF-1α蛋白积累需要基本的核因子-kappa B活性。IKK-β缺乏导致包括血管内皮生长因子在内的HIF-1α靶基因的缺陷诱导。IKK-β对于HIF-1α在经历细菌感染的巨噬细胞中的积累也是必不可少的。因此，IKK-β是低氧反应的重要生理因素，将其与先天免疫和炎症联系在一起。
The hypoxic response is an ancient stress response triggered by low ambient oxygen ( O(2)) ( ref. 1) and controlled by hypoxia-inducible transcription factor- 1 ( HIF- 1), whose a subunit is rapidly degraded under normoxia but stabilized when O(2)- dependent prolyl hydroxylases ( PHDs) that target its O(2)- dependent degradation domain are inhibited(2-4). Thus, the amount of HIF-1 alpha, which controls genes involved in energy metabolism and angiogenesis, is regulated post- translationally. Another ancient stress response is the innate immune response, regulated by several transcription factors, among which NF-kappa B plays a central role(5,6). NF-kappa B activation is controlled by I kappa B kinases ( IKK), mainly IKK-beta, needed for phosphorylation- induced degradation of I kappa B inhibitors in response to infection and inflammation(7). IKK-beta is modestly activated in hypoxic cell cultures when PHDs that attenuate its activation are inhibited(8). However, defining the relationship between NF-kappa B and HIF-1 alpha has proven elusive. Using in vitro systems, it was reported that HIF-1 alpha activates NF- kappa B(9), that NF-kappa B controls HIF-1 alpha transcription(10) and that HIF-1 alpha activation may be concurrent with inhibition of NF-kappa B(11). Here we show, with the use of mice lacking IKK-beta in different cell types, that NF-kappa B is a critical transcriptional activator of HIF-1 alpha and that basal NF-kappa B activity is required for HIF-1 alpha protein accumulation under hypoxia in cultured cells and in the liver and brain of hypoxic animals. IKK-beta deficiency results in defective induction of HIF-1 alpha target genes including vascular endothelial growth factor. IKK-beta is also essential for HIF-1 alpha accumulation in macrophages experiencing a bacterial infection. Hence, IKK-beta is an important physiological contributor to the hypoxic response, linking it to innate immunity and inflammation.