Leukocyte adhesion during hypoxia is mediated by HIF-1-dependent induction of β 2 integrin gene expression
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Inflammatory responses are associated with significant changes in tissue metabolism. In particular, metabolic shifts during inflammation can result in significant tissue hypoxia, with resultant induction of hypoxia-responsive genes. Given this association, we hypothesized that leukocyte functional responses are influenced by hypoxia. Initial experiments revealed that exposure of the promonocytic cell line U937 to hypoxia resulted in increased adhesion to activated endothelia. Such increases were transcription-dependent and were blocked by antibodies directed against β 2 , but not β 1 , integrins. Analysis of β 2 integrin mRNA and protein in U937 cells revealed a 5- to 6-fold increase with hypoxia. Extension of this analysis to hypoxic human whole blood revealed prominent induction of β 2 integrin mRNA and protein ex vivo . Furthermore, murine β 2 integrin mRNA was found to be significantly induced during hypoxia in vivo . Subsequent studies identified a binding site for hypoxia-inducible factor 1 (HIF-1) in the CD18 gene. This gene encodes the subunit common to all four known types of β 2 integrin heterodimer. HIF-1 binding was demonstrated in vivo , and mutational analysis of the HIF-1 site within the CD18 promoter resulted in a loss of hypoxia inducibility. Taken together, these results demonstrate that hypoxia induces leukocyte β 2 integrin expression and function by transcriptional mechanisms dependent upon HIF-1.
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HIF-1α transcriptionally controls the β2 integrin (CD18), important in all myeloid cell adhesion and transmigration.
“Finally, compelling evidence have revealed that HIF-1α transcriptionally controls the critical integrin important in all myeloid cell adhesion and transmigration, namely the β2 integrin (CD18)34,35.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [34]
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Self-citation
- Authors
- Kong, T., Eltzschig, H. K., Karhausen, J., Colgan, S. P., & Shelley, C. S.
- Affiliations
- Brigham and Women's Hospital (US)
- Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; Department of Anesthesiology and Intensive Care Medicine, University Hospital, Tübingen, D-72076, Germany; and Renal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129
- Corresponding author
- Colgan, Sean P.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-07-02
- Volume
- 101
- Issue
- 28
- Pages
- 10440-10445
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC478589
- OpenAlex
- W2096468570
- Cited by
- 242
- References
- 60
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 7 · 2023: 7 · 2022: 12 · 2021: 11 · 2020: 4 · 2019: 5 · 2018: 7 · 2017: 9 · 2016: 13 · 2015: 8 · 2014: 11 · 2013: 10 · 2012: 9
- FWCI
- 9.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health (DK-50305, DK-50189)
- National Heart, Lung, and Blood Institute (R01HL060569, HL-60569)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK050189, DK-50305, R37DK050189, R29DK050189, P01DK050305, DK-50189)
- Topics
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- leukocyte adhesion, hypoxia, HIF-1, beta2 integrins, CD18, integrin expression, transcriptional regulation, inflammation, tissue hypoxia, U937 cells, whole blood, promoter binding sites
- MeSH terms
- Hypoxia, Base Sequence, Cell Adhesion, DNA-Binding Proteins, Endothelium, Vascular, Humans, Leukocytes, Membrane Proteins, Molecular Sequence Data, Nuclear Proteins, Promoter Regions, Genetic, RNA, Messenger, Transcription Factors, Transcriptional Activation, Gene Expression, CD18 Antigens, U937 Cells, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit
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