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Hypoxia-Inducible Factor Augments Experimental Colitis Through an MIF–Dependent Inflammatory Signaling Cascade
Open accessAbstract
Background & aims Colon epithelial cells are critical for barrier function and contain a highly developed immune response. A previous study has shown hypoxia-inducible factor (HIF) as a critical regulator of barrier protection during colon epithelial injury. However, the role of HIF signaling in colon mucosal immunity is not known.Methods With the use of cre/loxP technology, intestinal-specific disruption of von Hippel-Lindau tumor suppressor protein (Vhl), hypoxia-inducible factor (Hif)-1alpha, and aryl hydrocarbon nuclear translocator (Arnt) was generated. Colon inflammation was induced using a dextran sulfate sodium (DSS)-induced colitis model, and the mice were analyzed by histologic analysis, Western blot analysis, and quantitative polymerase chain reaction.Results In mice, colonic epithelium disruption of Vhl resulted in constitutive expression of HIF, which initiated an increase in inflammatory infiltrates and edema in the colon. These effects were ameliorated in mice by disruption of both Vhl and Arnt/Hif1beta (which inactivates HIF). In a DSS-induced colitis model, increased HIF expression correlated with more severe clinical symptoms and an increase in histologic damage, while disruption of both Vhl and Arnt in the colon epithelium inhibited these effects. Furthermore, colons with constitutive activation of HIF displayed increased expression of proinflammatory mediators that were synergistically potentiated following DSS administration and reduced by inhibition of the proinflammatory and direct HIF target gene macrophage migration inhibitory factor.Conclusions The present study shows that a chronic increase in HIF signaling in the colon epithelial cells initiates a hyperinflammatory reaction that may have important implications in developing therapeutic strategies for inflammatory bowel disease.
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“These findings may be somewhat model-dependent, since epithelial HIF-based signaling has also been shown to promote inflammation in another study27.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [27]
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Metadata
- Authors
- Shah, Y. M., Ito, S., Morimura, K., Chen, C., Yim, S., Haase, V. H., & Gonzalez, F. J.
- Affiliations
- National Institutes of Health (US)
- University of Pennsylvania (US)
- Corresponding author
- Gonzalez, Frank J.
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2008-06
- Volume
- 134
- Issue
- 7
- Pages
- 2036-2048.e3
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC2533811
- OpenAlex
- W1989538067
- Cited by
- 168
- References
- 55
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 5 · 2023: 8 · 2022: 7 · 2021: 10 · 2020: 11 · 2019: 8 · 2018: 5 · 2017: 11 · 2016: 11 · 2015: 12 · 2014: 10 · 2013: 14 · 2012: 12
- FWCI
- 6.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (Z01BC005561, R01CA100787)
- Topics
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Life Sciences › Immunology and Microbiology › Immunology › Macrophage Migration Inhibitory Factor
- Health Sciences › Medicine › Gastroenterology › Microscopic Colitis
- Keywords
- hypoxia-inducible factor, HIF-1α, ARNT, VHL, macrophage migration inhibitory factor, DSS-induced colitis, experimental colitis, colonic epithelium, mucosal immunity, inflammatory bowel disease, intestinal inflammation, pro-inflammatory mediators
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Colitis, Colon, Disease Models, Animal, Enzyme Inhibitors, Gene Expression Regulation, Intestinal Mucosa, Isoxazoles, Macrophage Migration-Inhibitory Factors, Mice, Transgenic, Recombination, Genetic, Time Factors, Signal Transduction, Dextran Sulfate, Inflammation Mediators, Integrases, Intramolecular Oxidoreductases, Mice, Aryl Hydrocarbon Receptor Nuclear Translocator, Basic Helix-Loop-Helix Proteins, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit
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