Differential activation and antagonistic function of HIF-{alpha} isoforms in macrophages are essential for NO homeostasis.

By Norihiko Takeda, Ellen L O'Dea, A. Doedens, Jung-whan Kim, A. Weidemann, C. Stockmann, M. Asagiri, M. C. Simon, Alexander Hoffmann, Richard J. Johnson. Genes & Development, 2010

642 citations recorded by the source corpus.

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.

Subfields: Biochemistry, Cancer Research, Immunology

View Paper: https://www.semanticscholar.org/paper/0d1e0e9a9fa06f145ed557ff68171b0ec8a66886

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Biochemistry

1. Silvia Galván-Peña
2. Luke A. O'Neill

In Cancer Research

1. D. Hanahan
2. A. Mantovani
3. Lisa M. Coussens
4. A. Sica
5. Ke Zen
6. Hongwei Liang
7. Nan Wang
8. G. Semenza

In Immunology

1. A. Mantovani
2. A. Sica
3. D. Hanahan
4. Lisa M. Coussens
5. Ke Zen
6. Hongwei Liang
7. Nan Wang
8. G. Semenza

Citations in the corpus

• Macrophage plasticity and polarization: in vivo veritas. (2012, positive): “The hypoxia-inducible factors HIF-1α and HIF-2α are expressed differentially in M1- and M2-polarized macrophages (31) and regulate inducible NOS2 (M1) and arginase 1 (M2), respectively.”
• Hypoxia-Inducible Factors in Physiology and Medicine (2012, background): “Functional antagonism has also been reported in the regulation of nitric oxide (Takeda et al., 2010) and VEGF (Eubank et al.”
• Accessories to the crime: functions of cells recruited to the tumor microenvironment. (2012, positive): “Notably, differential expression of HIFs by endothelial cells (and IICs) is particularly significant for metastasis (Branco-Price et al., 2012; Takeda et al., 2010), as they variably alter vascular tension and function, largely dependent on nitric oxide, which, in turn, loosens pericyte coverage…”
• Molecular Mechanisms That Influence the Macrophage M1–M2 Polarization Balance (2014, background): “Together, these findings suggest HIFs as an important regulator of macrophage polarization, although a detailed dissection of whether the alteration of HIF isoform expression can switch macrophage phenotypes needs further investigation.”
• Metabolic Reprograming in Macrophage Polarization (2014, background): “Under hypoxic conditions, nitric oxide production through iNOS is HIF1α-dependent thus implicating HIF1α in bacterial clearance (24).”