Potentiation of Glucocorticoid Activity in Hypoxia through Induction of the Glucocorticoid Receptor

Leonard, Martin O; Godson, Catherine; Brady, Hugh R; Taylor, Cormac T

doi:10.4049/jimmunol.174.4.2250

Cited by 100Estrogen and related hormone effectsAdrenal Hormones and DisordersStress Responses and Cortisol

Potentiation of Glucocorticoid Activity in Hypoxia through Induction of the Glucocorticoid Receptor

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Leonard, Martin O, Godson, Catherine, Brady, Hugh R, Taylor, Cormac T·2005·The Journal of Immunology

DOI 10.4049/jimmunol.174.4.2250

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Abstract

Tissue hypoxia is intimately associated with chronic inflammatory disease and may signal to the resolution of inflammatory processes. Glucocorticoid signaling through the glucocorticoid receptor (GR) represents a clinically important endogenous anti-inflammatory pathway. Microarray analysis reveals that the GR is transcriptionally up-regulated by hypoxia in human renal proximal tubular epithelial cells. Hypoxic up-regulation of the GR was confirmed at the level of promoter activity, mRNA, and protein expression. Furthermore, functional potentiation of glucocorticoid activity in hypoxia was observed as an enhancement of dexamethasone-induced glucocorticoid response element promoter activity and enhanced dexamethasone-mediated inhibition of IL-1β-stimulated IL-8 expression and hypoxia-induced vascular endothelial growth factor expression. Knockdown of enhanced GR gene expression in hypoxia using specific GR small inhibitory RNA (siRNA) resulted in an attenuation of the enhanced glucocorticoid sensitivity. A role for the hypoxia-inducible transcription factor, HIF-1α, in the regulation of GR expression and the associated potentiation of glucocorticoid activity in hypoxia was also demonstrated. These results reveal a novel signaling aspect responsible for the incorporation of hypoxic and glucocorticoid stimuli, which we hypothesize to be an important co-operative pathway for the control of gene expression observed in complex tissue microenvironments in inflamed states.

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The IC50-DEX-hypoxanthine correlation indicates an association of immune GR sensitivity with hypoxia.
“Moreover, IC50-DEX showed a significant correlation with hypoxanthine indicating an association of immune GR sensitivity with hypoxia (40).”
From Mechanistic inferences on metabolic dysfunction in posttraumatic stress disorder from an integrated model and multiomic analysis: role of glucocorticoid receptor sensitivity (2019) · cites this paper as [40]
The section “Hypoxia causes a potentiation of glucocorticoid-dependent activity” reports a lower dexamethasone IC50 after hypoxia exposure (0.4 nM versus 7.5 nM in normoxia), supporting a link between hypoxia and glucocorticoid sensitivity. It does not report a correlation between IC50-DEX and hypoxanthine, so the specific basis the citing sentence gives for that link is unsupported. (LLM, conf=0.87)
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Authors: Leonard, M. O., Godson, C., Brady, H. R., & Taylor, C. T.
Affiliations: University College Dublin (IE)
ORCID: Leonard, Martin O
Godson, Catherine
Taylor, Cormac T
Venue: The Journal of Immunology
Publisher: Oxford University Press (OUP)
Published: 2005-02
Volume: 174
Issue: 4
Pages: 2250-2257
ISSN: 0022-1767 (ISSN-L)
1550-6606
DOI: 10.4049/jimmunol.174.4.2250
OpenAlex: W1674797587
Semantic Scholar: 8ce4d2e52c67aecd5a1a6dc3476b70445227e4ea
Cited by: 100
References: 48
Citations by year: 2026: 2 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 8 · 2020: 3 · 2019: 3 · 2018: 5 · 2017: 6 · 2016: 5 · 2015: 3 · 2014: 5 · 2013: 9 · 2012: 4
FWCI: 3.06
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations: The Journal of Immunology (publishedVersion)
PubMed (publishedVersion)
Funders: Wellcome Trust
Health Research Board
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords: glucocorticoid receptor, tissue hypoxia, HIF-1α, renal proximal tubular epithelial cells, anti-inflammatory signaling, IL-8 expression, vascular endothelial growth factor, siRNA knockdown, chronic inflammation, gene expression regulation
MeSH terms: Cell Line, Dexamethasone, DNA-Binding Proteins, Glucocorticoids, Humans, Nuclear Proteins, Promoter Regions, Genetic, Protein Binding, Receptors, Glucocorticoid, Transcription Factors, Transfection, Signal Transduction, Cell Hypoxia, Up-Regulation, Inflammation Mediators, Response Elements, Vascular Endothelial Growth Factor A, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit

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Potentiation of Glucocorticoid Activity in Hypoxia through Induction of the Glucocorticoid Receptor

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