Rius Jordi, Guma Monica, Schachtrup Christian, Akassoglou Katerina, Zinkernagel Annelies S, Nizet Victor, Johnson Randall S, Haddad Gabriel G, Karin Michael
Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0723, USA.
Nature. 2008 Jun 5;453(7196):807-11. doi: 10.1038/nature06905. Epub 2008 Apr 23.
The hypoxic response is an ancient stress response triggered by low ambient oxygen (O2) (ref. 1) and controlled by hypoxia-inducible transcription factor-1 (HIF-1), whose alpha subunit is rapidly degraded under normoxia but stabilized when O2-dependent prolyl hydroxylases (PHDs) that target its O2-dependent degradation domain are inhibited. Thus, the amount of HIF-1alpha, 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-kappaB plays a central role. NF-kappaB activation is controlled by IkappaB kinases (IKK), mainly IKK-beta, needed for phosphorylation-induced degradation of IkappaB inhibitors in response to infection and inflammation. IKK-beta is modestly activated in hypoxic cell cultures when PHDs that attenuate its activation are inhibited. However, defining the relationship between NF-kappaB and HIF-1alpha has proven elusive. Using in vitro systems, it was reported that HIF-1alpha activates NF-kappaB, that NF-kappaB controls HIF-1alpha transcription and that HIF-1alpha activation may be concurrent with inhibition of NF-kappaB. Here we show, with the use of mice lacking IKK-beta in different cell types, that NF-kappaB is a critical transcriptional activator of HIF-1alpha and that basal NF-kappaB activity is required for HIF-1alpha 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-1alpha target genes including vascular endothelial growth factor. IKK-beta is also essential for HIF-1alpha 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.
缺氧反应是一种古老的应激反应，由低环境氧（O2）触发（参考文献1），并由缺氧诱导转录因子-1（HIF-1）控制，其α亚基在常氧条件下迅速降解，但当靶向其氧依赖性降解结构域的氧依赖性脯氨酰羟化酶（PHD）被抑制时则会稳定下来。因此，控制参与能量代谢和血管生成的基因的HIF-1α的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NF-κB起核心作用。NF-κB的激活由IκB激酶（IKK）控制，主要是IKK-β，它是响应感染和炎症时磷酸化诱导IκB抑制剂降解所必需的。当减弱其激活的PHD被抑制时，IKK-β在缺氧细胞培养物中被适度激活。然而，确定NF-κB与HIF-1α之间的关系已被证明是难以捉摸的。使用体外系统，有报道称HIF-1α激活NF-κB，NF-κB控制HIF-1α转录，并且HIF-1α激活可能与NF-κB的抑制同时发生。在这里，我们通过使用在不同细胞类型中缺乏IKK-β的小鼠表明，NF-κB是HIF-1α的关键转录激活因子，并且基础NF-κB活性是缺氧动物的培养细胞以及肝脏和大脑中缺氧条件下HIF-1α蛋白积累所必需的。IKK-β缺陷导致包括血管内皮生长因子在内的HIF-1α靶基因的诱导缺陷。IKK-β对于经历细菌感染的巨噬细胞中HIF-1α的积累也至关重要。因此，IKK-β是缺氧反应的重要生理贡献者，将其与先天免疫和炎症联系起来。
