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NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α
Open accessAbstract
The hypoxic response is an ancient stress response triggered by low ambient oxygen (O2) (ref. 1) and controlled by hypoxia-inducible transcription factor-1 (HIF-1), whose alpha subunit is rapidly degraded under normoxia but stabilized when O2-dependent prolyl hydroxylases (PHDs) that target its O2-dependent degradation domain are inhibited. Thus, the amount of HIF-1alpha, which controls genes involved in energy metabolism and angiogenesis, is regulated post-translationally. Another ancient stress response is the innate immune response, regulated by several transcription factors, among which NF-kappaB plays a central role. NF-kappaB activation is controlled by IkappaB kinases (IKK), mainly IKK-beta, needed for phosphorylation-induced degradation of IkappaB inhibitors in response to infection and inflammation. IKK-beta is modestly activated in hypoxic cell cultures when PHDs that attenuate its activation are inhibited. However, defining the relationship between NF-kappaB and HIF-1alpha has proven elusive. Using in vitro systems, it was reported that HIF-1alpha activates NF-kappaB, that NF-kappaB controls HIF-1alpha transcription and that HIF-1alpha activation may be concurrent with inhibition of NF-kappaB. Here we show, with the use of mice lacking IKK-beta in different cell types, that NF-kappaB is a critical transcriptional activator of HIF-1alpha and that basal NF-kappaB activity is required for HIF-1alpha protein accumulation under hypoxia in cultured cells and in the liver and brain of hypoxic animals. IKK-beta deficiency results in defective induction of HIF-1alpha target genes including vascular endothelial growth factor. IKK-beta is also essential for HIF-1alpha accumulation in macrophages experiencing a bacterial infection. Hence, IKK-beta is an important physiological contributor to the hypoxic response, linking it to innate immunity and inflammation.
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“Additionally, numerous studies have shown that NF-κB regulates the hypoxic response by stimulating the transcription of HIF-1α and HIF-1β, and by inducing IKK-dependent stabilization of HIF-2α [15–17].”
From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [15]
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“The ERN1 and CAPG genes might also be involved in the innate immune response since hypoxia triggers innate immunity responses through the activation of the hypoxia induced factor α1 (HIF-1α) (Oosthuyse et al., 2001; Rius et al., 2008; Singh et al., 2016).”
From Identification of Candidate Signature Genes and Key Regulators Associated With Trypanotolerance in the Sheko Breed (2019) · cites this paper as Rius et al., 2008
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“HIF-1α activation acts in concert with NF-κB activation and boosts antimicrobial immunity (Nizet and Johnson, 2009;Rius et al., 2008).”
From Iron in infection and immunity (2020) · cites this paper as Rius et al., 2008
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“In macrophages, lipopolysaccharide (LPS)-induced HIF1 a accumulation requires nuclear factor (NF)k B- and p42/44 MAPK-dependent transcriptional events (Frede et al., 2006; Rius et al., 2008).”
From Ferritin-Mediated Iron Sequestration Stabilizes Hypoxia-Inducible Factor-1α upon LPS Activation in the Presence of Ample Oxygen (2015) · cites this paper as Rius et al., 2008
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“NF-kB, which is a master regulator of inflammatory responses, is essential for the induction of baseline Hif-1α mRNA [55]”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [55]
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“Recent studies indicate that transcription of HIF-1α is activated by NF-κB-mediated signaling51.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [51]
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Self-citation
Metadata
- Authors
- Rius, J., Guma, M., Schachtrup, C., Akassoglou, K., Zinkernagel, A. S., Nizet, V., Johnson, R. S., Haddad, G. G., & Karin, M.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Karin, Michael
- ORCID
- Venue
- Nature
- Published
- 2008-04-23
- Volume
- 453
- Issue
- 7196
- Pages
- 807-811
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2669289
- OpenAlex
- W2162121911
- Cited by
- 1,614
- References
- 34
- Citations by year
- 2026: 89 · 2025: 85 · 2024: 79 · 2023: 78 · 2022: 81 · 2021: 107 · 2020: 79 · 2019: 77 · 2018: 82 · 2017: 70 · 2016: 97 · 2015: 95 · 2014: 105 · 2013: 91 · 2012: 89
- FWCI
- 35.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA118165)
- National Institute of Allergy and Infectious Diseases (R01AI043477)
- National Center for Research Resources (P41RR004050)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- NF-κB, HIF-1α, hypoxia response, innate immunity, IKKβ, transcriptional regulation, prolyl hydroxylase, oxygen-dependent degradation, inflammation, liver, brain, hypoxia-inducible factor, IκB kinase, oxygen sensing
- MeSH terms
- Animals, Hypoxia, Brain, Gene Expression Regulation, Immunity, Innate, Inflammation, Liver, Macrophages, Transcription, Genetic, Cell Hypoxia, NF-kappa B, Mice, I-kappa B Kinase, Hypoxia-Inducible Factor 1, alpha Subunit
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