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Published ahead of print on June 7, 2004, doi:10.1164/rccm.200308-1143OC

Am. J. Respir. Crit. Care Med., Volume 170, Number 4, August 2004, 420-425

A more recent version of this article appeared on August 15, 2004
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Submitted on August 16, 2003
Accepted on May 30, 2004

Glucocorticoid Receptor Isoforms {alpha} and {beta} in In Vitro Cytokine-induced Glucocorticoid Insensitivity

Alfons Torrego1, Laura Pujols2, Jordi Roca-Ferrer2, Joaquim Mullol3, Antoni Xaubet1, and Cesar Picado1*

1 Servei de Pneumologia i Al-lergia Respiratoria, Universitat de Barcelona, Institut Clinic de Pneumologia i Cirurgia Toracica, Barcelona, Spain; Departament de Medicina, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, 2 Departament de Medicina, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, 3 Servei d'Otorinolaringologia, Universitat de Barcelona, Hospital Clinic, Barcelona, Spain; Departament de Medicina, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

* To whom correspondence should be addressed. E-mail: axaubet{at}medicina.ub.es.

We stimulated peripheral blood mononuclear cells from 14 healthy subjects, 14 stable asthmatics and 13 unstable asthmatics with IL-2 and IL-4 to induce glucocorticoid insensitivity and we examined the relationship between insensitivity and the expression of glucocorticoid receptor (GR) isoforms. Results are expressed as mean±SD nM of IC50 in proliferation assays and as mean±SD of 103 cDNA molecules/µg total RNA in real-time PCR analysis. Cells from unstable asthmatics were less sensitive (316±7 nM) to dexamethasone antiproliferative effects than those from healthy controls (102±4 nM, p<0.05) and stable asthmatics (107±2 nM, p<0.05). Co-incubation with IL-2 and IL-4 repressed the inhibitory effect of dexamethasone on proliferation in all groups (unstable: 851±47 nM, p<0.01; stable: 912±52 nM, p=0.001; controls: 537±45 nM, p=0.001). GR-{alpha} mRNA baseline expression was higher in unstable (1.95±0.40, p<0.05) than in stable asthmatics (1.46±0.35) and healthy subjects (1.35±0.25). GR-{beta} mRNA was 600 times lower than GR-{alpha} in the three groups. Co-incubation with IL-2 and IL-4 significantly increased GR-{alpha} mRNA expression in the three groups (p<0.01) but caused no significant change in GR-{beta} mRNA. GR-{alpha}, but not GR-{beta} protein, was detected at baseline and after cytokine exposure. Our data do not support the hypothesis that increased GR-{beta} expression can contribute to cytokine-induced glucocorticoid insensitivity.
Key words: Asthma, IL-2,IL-4, PBMC, glucocorticoid receptor




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