title: Differential activation and antagonistic function of HIF-{alpha} isoforms in macrophages are essential for NO homeostasis.
abstract: 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.
authors.affiliation: University of California at San Diego, La Jolla, 92093, USA.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Takeda
authors.forename: Ellen L
authors.initials: EL
authors.lastname: O'Dea
authors.forename: Andrew
authors.initials: A
authors.lastname: Doedens
authors.forename: Jung-whan
authors.initials: JW
authors.lastname: Kim
authors.forename: Alexander
authors.initials: A
authors.lastname: Weidemann
authors.forename: Christian
authors.initials: C
authors.lastname: Stockmann
authors.forename: Masataka
authors.initials: M
authors.lastname: Asagiri
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D003198:Computer Simulation; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D020033:Protein Isoforms; D018417:Th1 Cells; D018418:Th2 Cells; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D001119:Arginase; D051792:Basic Helix-Loop-Helix Proteins; D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D020033:Protein Isoforms; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C544448:Arg1 protein, mouse