Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis
Open accessAbstract
Mucosal epithelial cells are uniquely equipped to maintain barrier function even under adverse conditions. Previous studies have implicated hypoxia in mucosal tissue damage resulting from both acute and chronic inflammation. Given the importance of the transcriptional regulator hypoxia-inducible factor-1 (HIF-1) for adaptive hypoxia responses, we hypothesized that HIF-1 may serve as a barrier-protective element during mucosal inflammation. Initial studies of hapten-based murine colitis revealed extensive mucosal hypoxia and concomitant HIF-1 activation during colitis. To study this in more detail, we generated 2 mouse lines with intestinal epithelium–targeted expression of either mutant Hif1a (inability to form HIF-1) or mutant von Hippel-Lindau gene (Vhlh; constitutively active HIF-1). Studies of colitis in these mice revealed that decreased HIF-1 expression correlated with more severe clinical symptoms (mortality, weight loss, colon length), while increased HIF levels were protective in these parameters. Furthermore, colons with constitutive activation of HIF displayed increased expression levels of HIF-1–regulated barrier-protective genes (multidrug resistance gene-1, intestinal trefoil factor, CD73), resulting in attenuated loss of barrier during colitis in vivo. Taken together, these studies provide insight into tissue microenvironmental changes during model inflammatory bowel disease and identify HIF-1 as a critical factor for barrier protection during mucosal insult.
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Expression of HIF-1 is induced in inflammatory lesions.
“The same series of studies which identified inflammation-related hypoxia also showed that expression of HIF-1 is induced in the inflammatory lesions13.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [13]
Studies of active inflammation in mouse models of IBD have shown the intestinal epithelial cell to be a primary target for hypoxia.
“In addition, studies of active inflammation in mouse models of IBD have shown the intestinal epithelial cell to be a primary target for hypoxia13.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [13]
Loss of epithelial HIF-1α results in a more severe colitic phenotype than wild-type animals, with increased weight loss, decreased colon length and increased epithelial permeability, whereas constitutively active intestinal epithelial HIF is protective for these parameters.
“Loss of epithelial HIF-1α resulted in a more severe colitic phenotype than wild-type animals, with increased weight loss, decreased colon length and increased epithelial permeability, whereas constitutively active intestinal epithelial HIF was protective for these parameters.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [13]
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Self-citation
- Authors
- Karhausen, J., Furuta, G. T., Tomaszewski, J. E., Johnson, R. S., Colgan, S. P., & Haase, V. H.
- Affiliations
- Brigham and Women's Hospital (US)
- University of Pennsylvania (US)
- University of California San Diego (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2004-10-15
- Volume
- 114
- Issue
- 8
- Pages
- 1098-1106
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC522241
- OpenAlex
- W1982920345
- Cited by
- 655
- References
- 60
- Citations by year
- 2026: 19 · 2025: 25 · 2024: 25 · 2023: 43 · 2022: 29 · 2021: 35 · 2020: 41 · 2019: 37 · 2018: 32 · 2017: 38 · 2016: 46 · 2015: 40 · 2014: 29 · 2013: 44 · 2012: 37
- FWCI
- 7.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Crohn's and Colitis Foundation of America
- Massachusetts Institute of Technology
- Crohn's and Colitis Foundation
- National Institutes of Health (DE13499, DK-50189, PO1 DE13499)
- National Heart, Lung, and Blood Institute (R01HL060569, HL-60569)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK002668, DK02668, R01DK050189, DK062060, R03DK062060, R37DK050189, R29DK050189, DK-50189)
- National Institute of Dental and Craniofacial Research (P01 DE 13499, P01DE013499)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
- Keywords
- HIF-1, colitis, intestinal epithelium, mucosal barrier, intestinal hypoxia, inflammatory bowel disease, VHL, HIF1A, intestinal epithelial cells, TFF3, CD73, multidrug resistance gene 1, epithelial protection
- MeSH terms
- Animals, Carrier Proteins, Colitis, DNA-Binding Proteins, Gene Expression Regulation, Humans, Intestinal Mucosa, Mice, Inbred Strains, Mice, Transgenic, Nuclear Proteins, Recombination, Genetic, Transcription Factors, Cell Hypoxia, Gene Deletion, Genes, Reporter, Mice, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit
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