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

摘要: Hypoxic response and inflammation both involve the action of hypoxia-inducible transcription factors HIF-1α HIF-2α. Previous studies have revealed that HIF-α proteins are in a number aspects similarly regulated post-translationally. However, functional interrelationship these two isoforms remains largely unclear. The polarization macrophages controls functionally divergent processes; one is nitric oxide (NO) production, which turn controlled part by HIF factors. We show here can be differentially activated: induced Th1 cytokines M1 macrophage polarization, whereas HIF-2α Th2 during an M2 response. This differential was most evident polarized through isoform-specific regulation inducible NO synthase gene HIF-1α, arginase1 In silico modeling predicted overall availability due to versus HIF-2α, acting to, respectively, either increase or suppress synthesis. An vivo model endotoxin challenge confirmed this; thus, reveal homologous factors, physiologically antagonistic functions, but their antiphase allows them coordinately regulate production cytokine-induced transcription-dependent fashion.