Differential activation and antagonistic function of HIF-α isoforms in macrophages are essential for NO homeostasis

N Takeda, EL O'Dea, A Doedens, J Kim… - Genes & …, 2010 - genesdev.cshlp.org
N Takeda, EL O'Dea, A Doedens, J Kim, A Weidemann, C Stockmann, M Asagiri, MC Simon
Genes & development, 2010genesdev.cshlp.org
Hypoxic response and inflammation both involve the action of the hypoxia-inducible
transcription factors HIF-1α and HIF-2α. Previous studies have revealed that both HIF-α
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-α …
Hypoxic response and inflammation both involve the action of the hypoxia-inducible transcription factors HIF-1α and HIF-2α. Previous studies have revealed that both HIF-α 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-α isoforms can be differentially activated: HIF-1α is induced by Th1 cytokines in M1 macrophage polarization, whereas HIF-2α is induced by Th2 cytokines during an M2 response. This differential response was most evident in polarized macrophages through HIF-α isoform-specific regulation of the inducible NO synthase gene by HIF-1α, and the arginase1 gene by HIF-2α. In silico modeling predicted that regulation of overall NO availability is due to differential regulation of HIF-1α versus HIF-2α, 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-1α and HIF-2α, 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.
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