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 accessAbstract
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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Cites
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Self-citation
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Sica, A., & Mantovani, A. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59643 · Cited by 6,335
Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment
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Hypoxia-inducible factors and the response to hypoxic stress
Majmundar, A. J., Wong, W. J., & Simon, M. C. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.022 · Cited by 2,380
Self-citationMetabolic reprogramming in macrophages and dendritic cells in innate immunity
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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
- OpenAlex
- W1981253971
- Cited by
- 623
- References
- 21
- Type
- posted content
- Language
- en
- Open access
- diamond
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- 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. (2010). Differential activation and antagonistic function of HIF-α isoforms in macrophages are essential for NO homeostasis. Genes & Development. https://doi.org/10.1101/gad.1881410
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