CoChat
Sign Up
Cited by 1,614NF-κB Signaling PathwaysCancer, Hypoxia, and MetabolismSignaling Pathways in Disease

NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α

Open access
Rius, Jordi, Guma, Monica, Schachtrup, Christian, Akassoglou, Katerina, Zinkernagel, Annelies S., Nizet, Victor, Johnson, Randall S., Haddad, Gabriel G. +1 more·2008·Nature
DOI 10.1038/nature06905PMC PMC2669289
Open this paper in CoChat — free accountOpen PDF

Abstract

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/nature06905

Cites

34 of 34 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • NF-κB regulates the hypoxic response by stimulating HIF-1α and HIF-1β transcription and by IKK-dependent stabilization of HIF-2α.

    “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]

    The paper’s main text (page unavailable) reports that IKKβ-responsive NF-κB activates HIF-1α transcription, supporting that part of the claim. It does not establish HIF-1β transcriptional stimulation; moreover, it reports that IKKβ was required for HIF-1α accumulation but not HIF-2α accumulation in the macrophages studied, contrary to the HIF-2α part. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • The ERN1 and CAPG genes might also be involved in the innate immune response since hypoxia triggers innate immunity responses through the activation of HIF-1α.

    “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

    In the main text (page unavailable), Rius et al. report that hypoxia promotes HIF-1α accumulation and that the hypoxic response supports macrophages and neutrophils in infected tissue. They also describe HIF-1α as *suggested* to promote inflammatory cytokine expression in stimulated macrophages. This supports a link between hypoxia, HIF-1α and innate immunity, but not the broader assertion that hypoxia itself triggers innate immune responses through HIF-1α. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • HIF-1α activation acts in concert with NF-κB activation and boosts antimicrobial immunity.

    “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

  • In macrophages, LPS-induced HIF1α accumulation requires NFκB- and p42/44 MAPK-dependent transcriptional events.

    “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

  • NF-kB is essential for the induction of baseline Hif-1α mRNA.

    “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]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

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
Publisher
Springer Science and Business Media LLC
Published
2008-04-23
Volume
453
Issue
7196
Pages
807-811
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature06905
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
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review