Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid-resistant asthma

Title: Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid-resistant asthma
Authors: Adcock, IM
Lane, SJ
Brown, CR
Lee, TH
Barnes, PJ
Item Type: Journal Article
Abstract: Glucocorticosteroids are a very effective treatment for asthma and other chronic inflammatory diseases. However, a small proportion of patients is resistant to the therapeutic effects of glucocorticoids. Pharmacokinetic and ligand binding studies suggest that the molecular abnormality in steroid resistance lies distal to nuclear translocation. We have previously reported that there is a decreased ability of glucocorticoid receptors (GR) to bind to the DNA-binding site in peripheral blood mononuclear cells (PBMC) after dexamethasone treatment. This reduced DNA binding was due to a decrease in the number of receptors available rather than an alteration in affinity for DNA. To study this reduced DNA binding, we examined the ability of the nuclear translocated transcription factors activator protein-1 (AP-1), nuclear factor κB (NF-κB) and cyclic AMP response element-binding protein (CREB) to bind to their DNA-binding sites and to interact with GR in PBMC from patients with steroid-sensitive and steroid-resistant asthma. There was a significant reduction in the interaction between GR and AP-1 in these steroid-resistant patients, although interaction with other transcription factors activated in inflammation (NF-κB and CREB) was unaffected. An increase in the basal levels of AP-1 DNA binding was also detected in the nuclei from steroid-resistant asthmatic patients. There were no differences in the amount of messenger RNA detected for the components of AP-1, c-fos and c-Jun, nor in the sequences of these messenger RNAs. These results suggest either that the ability of the GR to bind to glucocorticoid response elements and AP-1 is altered in steroid-resistant patients or that increased levels of AP-1 prevent GR DNA binding, and that this may be the molecular basis of resistance to the antiinflammatory effect of steroids in these cells.
Issue Date: 1-Dec-1995
Date of Acceptance: 5-Jul-1995
URI: http://hdl.handle.net/10044/1/31751
DOI: http://dx.doi.org/10.1084/jem.182.6.1951
ISSN: 1540-9538
Publisher: Rockefeller University Press
Start Page: 1951
End Page: 1958
Journal / Book Title: Journal of Experimental Medicine
Volume: 182
Issue: 6
Copyright Statement: © 1995 Rockefeller University Press
Keywords: Asthma
Base Sequence
Cyclic AMP Response Element-Binding Protein
Dexamethasone
Drug Resistance
Gene Expression
Genes, fos
Genes, jun
Glucocorticoids
Humans
Male
Middle Aged
Molecular Sequence Data
NF-kappa B
Oligodeoxyribonucleotides
Prednisolone
RNA, Messenger
Receptors, Glucocorticoid
Tetradecanoylphorbol Acetate
Transcription Factor AP-1
Immunology
11 Medical And Health Sciences
Publication Status: Published
Appears in Collections:National Heart and Lung Institute
Airway Disease
Faculty of Medicine



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