Differential activation and antagonistic function of HIF-α isoforms in macrophages are essential for NO homeostasis
Differential activation and antagonistic function of HIF-α isoforms in macrophages are essential for NO homeostasis
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DOI：
10.1101/gad.1881410
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发表时间：
2010-03-01
影响因子：
10.5
通讯作者：
Johnson, Randall S.
中科院分区：
文献类型：
--
作者：
Takeda, Norihiko;O'Dea, Ellen L.;Johnson, Randall S.
缺氧反应和炎症都涉及缺氧诱导转录因子HIF-1 α和HIF-2 α的作用。以前的研究表明，这两种HIF-α蛋白在许多方面都受到类似的调节。然而，这两种异构体的功能相互关系在很大程度上仍然不清楚。巨噬细胞的极化控制功能上不同的过程;其中之一是一氧化氮（NO）的产生，这反过来又部分地由HIF因子控制。我们在这里表明，HIF-α亚型可以被差异激活：HIF-1 α是由M1巨噬细胞极化中的Th 1细胞因子诱导的，而HIF-2 α是由M2反应期间的Th 2细胞因子诱导的。这种差异反应在极化的巨噬细胞中最为明显，通过HIF-1 α对诱导型NO合酶基因的HIF-α亚型特异性调节，以及HIF-2 α对转录酶1基因的HIF-α亚型特异性调节。计算机模拟预测，总体NO可用性的调节是由于HIF-1 α与HIF-2 α的差异调节，分别起增加或抑制NO合成的作用。内毒素攻击的体内模型证实了这一点;因此，这些研究揭示了两种同源转录因子HIF-1 α和HIF-2 α可以具有生理拮抗功能，但是它们的反相调节允许它们以精氨酸诱导和转录依赖的方式协调调节NO的产生。
Hypoxic response and inflammation both involve the action of the hypoxia-inducible transcription factors HIF-1 alpha and HIF-2 alpha. Previous studies have revealed that both HIF-alpha proteins are in a number of aspects similarly regulated post-translationally. However, the functional interrelationship of these two isoforms remains largely unclear. The polarization of macrophages controls functionally divergent processes; one of these is nitric oxide (NO) production, which in turn is controlled in part by HIF factors. We show here that the HIF-alpha isoforms can be differentially activated: HIF-1 alpha is induced by Th1 cytokines in M1 macrophage polarization, whereas HIF-2 alpha is induced by Th2 cytokines during an M2 response. This differential response was most evident in polarized macrophages through HIF-alpha isoform-specific regulation of the inducible NO synthase gene by HIF-1 alpha, and the arginase1 gene by HIF-2 alpha. In silico modeling predicted that regulation of overall NO availability is due to differential regulation of HIF-1 alpha versus HIF-2 alpha, acting to, respectively, either increase or suppress NO synthesis. An in vivo model of endotoxin challenge confirmed this; thus, these studies reveal that the two homologous transcription factors, HIF-1 alpha and HIF-2 alpha, can have physiologically antagonistic functions, but that their antiphase regulation allows them to coordinately regulate NO production in a cytokine-induced and transcription-dependent fashion.