p38 Mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma
Abstract
Background Although glucocorticoids are the most effective treatment for chronic inflammatory diseases, such as asthma, some patients show a poor response. IL-2 combined with IL-4 can alter glucocorticoid receptor (GR) ligand-binding affinity and modulate glucocorticoid function. Objective We sought to confirm the altered ligand-binding affinity in a distinct group of steroid-dependent asthmatic subjects and examine the mechanism by which IL-2 and IL-4 modify the ligand-binding affinity of the GR. Methods We examined PBMCs from healthy subjects, subjects with mild asthma, and steroid-dependent subjects with severe asthma using dexamethasone-binding assays and Western blot analysis of GR and phosphorylated activated transcription factor 2 expression. GR phosphorylation was measured after orthophosphate labeling and immunoprecipitation and cytokine production by means of ELISA. Results GR ligand-binding affinity was reduced in the nucleus but not in the cytoplasm of steroid-dependent asthmatic subjects compared with that seen in healthy subjects (dissociation constant, 39.8 +/- 4.6 vs. 6.79 +/- 0.8 nmol/L). This difference in ligand-binding affinity could be mimicked by IL-2 and IL-4 cotreatment and was blocked by the p38 mitogen-activated kinase (MAPK) inhibitor SB203580. Activation of p38 MAPK by IL-2 and IL-4, as shown by means of phosphorylation of activated transcription factor 2, resulted in GR phosphorylation and reduced dexamethasone repression of LPS-stimulated GM-CSF…
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The effects of COX-2 inhibitors on GR may be related to inhibition of p38.
“indicating the effects of COX-2 inhibitors on GR may be related to inhibition of p38.49”
From Cytokines and Glucocorticoid Receptor Signaling (2009) · cites this paper as [49]
Anisomycin, a potent activator of p38, reversed the celecoxib-induced enhancement of GR-mediated gene transcription in a dose-dependent manner.
“we administered anisomycin, a potent activator of p38, along with celecoxib to rat PC12 cells. Anisomycin reversed the celecoxib-induced enhancement of GR-mediated gene transcription in a dose-dependent manner, indicating the effects of COX-2 inhibitors on GR may be related to inhibition of p38.49”
From Cytokines and Glucocorticoid Receptor Signaling (2009) · cites this paper as [49]
Treatment of rat PC12 cells with the COX-1 and COX-2 inhibitor ibuprofen, or the selective COX-2 inhibitor celecoxib, significantly increased GR-mediated gene transcription.
“studies from our group have found that treatment of rat PC12 cells with the COX-1 and COX-2 inhibitor, ibuprofen, or the selective COX-2 inhibitor, celecoxib, significantly increased GR-mediated gene transcription.”
From Cytokines and Glucocorticoid Receptor Signaling (2009) · cites this paper as [49]
MAPK signaling pathways (including both p38 and JNK) may be involved in the effects of COX-2 inhibition on GR function.
“Taken together, these results suggest that MAPK signaling pathways (including both p38 and JNK) may be involved in the effects of COX-2 inhibition on GR function.”
From Cytokines and Glucocorticoid Receptor Signaling (2009) · cites this paper as [49]
The selective COX-1 inhibitor valerylsalicylic acid had no effects on GR function.
“the same studies found that the selective COX-1 inhibitor, valerylsalicylic acid, had no effects on GR function.49”
From Cytokines and Glucocorticoid Receptor Signaling (2009) · cites this paper as [49]
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- Authors
- Irusen, E., Matthews, J. G., Takahashi, A., Barnes, P. J., Chung, K. F., & Adcock, I. M.
- Affiliations
- Imperial College London (GB)
- Venue
- Journal of Allergy and Clinical Immunology
- Publisher
- Elsevier BV
- Published
- 2002-04
- Volume
- 109
- Issue
- 4
- Pages
- 649-657
- ISSN
- 0091-6749 (ISSN-L)
- OpenAlex
- W2127186884
- Cited by
- 416
- References
- 0
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 10 · 2023: 10 · 2022: 8 · 2021: 17 · 2020: 16 · 2019: 12 · 2018: 5 · 2017: 14 · 2016: 17 · 2015: 18 · 2014: 25 · 2013: 29 · 2012: 27
- FWCI
- 14.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Allergy and Clinical Immunology (publishedVersion)
- PubMed (publishedVersion)
- SUNScholar (Stellenbosch University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- glucocorticoid receptor, p38 MAPK, glucocorticoid resistance, ligand binding affinity, interleukin-2, IL-4, glucocorticoid receptor phosphorylation, p38 MAPK inhibitor, dexamethasone, CD2+ T cells, IL-10, GM-CSF, severe asthma
- MeSH terms
- Administration, Oral, Adult, Asthma, Drug Resistance, Female, Forced Expiratory Volume, Glucocorticoids, Humans, Imidazoles, Interleukin-2, Male, Middle Aged, Phosphorylation, Pyridines, Receptors, Glucocorticoid, Interleukin-4, Granulocyte-Macrophage Colony-Stimulating Factor, Interleukin-10, Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases
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