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Cited by 623

The DOI matches its Crossref record; 21 of the 21 references it cites were found in a registry or an index.

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

Open access
Takeda, Norihiko, O'Dea, Ellen L., Doedens, Andrew, Kim, Jung-whan, Weidemann, Alexander, Stockmann, Christian, Asagiri, Masataka, Simon, M. Celeste, Hoffmann, Alexander, Johnson, Randall S.·2010·Genes & Development
DOI 10.1101/gad.1881410
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Abstract

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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Metadata

Authors
Takeda, N., O'Dea, E. L., Doedens, A., Kim, J.-W., Weidemann, A., Stockmann, C., Asagiri, M., Simon, M. C., Hoffmann, A., & Johnson, R. S.
Venue
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Published
2010-03-01
Volume
24
Issue
5
Pages
491-501
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
DOI
10.1101/gad.1881410
OpenAlex
W1981253971
Cited by
623
References
21
Type
posted content
Language
en
Open access
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