University of California at San Diego, La Jolla, 92093, USA.
Genes Dev. 2010 Mar 1;24(5):491-501. doi: 10.1101/gad.1881410.
Hypoxic response and inflammation both involve the action of the hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha. 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-1alpha is induced by Th1 cytokines in M1 macrophage polarization, whereas HIF-2alpha 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-1alpha, and the arginase1 gene by HIF-2alpha. In silico modeling predicted that regulation of overall NO availability is due to differential regulation of HIF-1alpha versus HIF-2alpha, 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-1alpha and HIF-2alpha, 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.
缺氧反应和炎症都涉及缺氧诱导转录因子 HIF-1α 和 HIF-2α 的作用。先前的研究表明，两种 HIF-α 蛋白在许多方面都受到类似的翻译后调控。然而，这两种同工型的功能相互关系在很大程度上仍不清楚。巨噬细胞的极化控制着功能上不同的过程；其中之一是一氧化氮 (NO) 的产生，而这部分又受到 HIF 因子的控制。我们在这里表明，HIF-α 同工型可以被差异激活：HIF-1α 在 M1 巨噬细胞极化时被 Th1 细胞因子诱导，而 HIF-2α 在 M2 反应时被 Th2 细胞因子诱导。这种差异反应在极化的巨噬细胞中最为明显，通过 HIF-1α 对诱导型一氧化氮合酶基因的 HIF-α 同工型特异性调节，以及 HIF-2α 对精氨酸酶 1 基因的调节。计算机模拟预测，整体 NO 可用性的调节是由于 HIF-1α 与 HIF-2α 的差异调节，分别增加或抑制 NO 合成。内毒素挑战的体内模型证实了这一点；因此，这些研究表明，两种同源转录因子 HIF-1α 和 HIF-2α 可以具有生理拮抗作用，但它们的反相位调节允许它们以细胞因子诱导和转录依赖的方式协调调节 NO 的产生。
