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Published ahead of print on June 7, 2004, doi:10.1164/rccm.200308-1143OC
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American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 420-425, (2004)
© 2004 American Thoracic Society

Original Article

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

Alfons Torrego, Laura Pujols, Jordi Roca-Ferrer, Joaquim Mullol, Antoni Xaubet and César Picado

Servei de Pneumologia i Al·lèrgia Respiratòria, Institut Clínic de Pneumologia i Cirurgia Toràcica, and Servei d'Otorinolaringologia, Hospital Clínic; and Institut d'Investigacions Biomèdiques August Pi i Sunyer, Departament de Medicina, Universitat de Barcelona, Barcelona, Spain

Correspondence and requests for reprints should be addressed to C. Picado, M.D., Servei de Pneumologia, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain. E-mail: cpicado{at}ub.edu

We stimulated peripheral blood mononuclear cells from 14 healthy subjects, 14 patients with stable asthma, and 13 patients with unstable asthma with interleukin (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 IC50 (nanomolar) values (means ± SD) in proliferation assays and as 103 cDNA molecules per microgram of total RNA (means ± SD) in real-time polymerase chain reaction analysis. Cells from patients with unstable asthma were less sensitive (316 ± 7 nM) to dexamethasone antiproliferative effects than those from healthy control subjects (102 ± 4 nM, p < 0.05) and patients with stable asthma (107 ± 2 nM, p < 0.05). Coincubation 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; control subjects: 537 ± 45 nM, p = 0.001). GR-{alpha} mRNA baseline expression was higher in patients with unstable asthma [(1.95 ± 0.40) x 103 cDNA molecules/µg total RNA, p < 0.05] than in patients with stable asthma [(1.46 ± 0.35) x 103 cDNA molecules/µg total RNA] and healthy subjects [(1.35 ± 0.25) x 103 cDNA molecules/µg total RNA]. GR-ß mRNA was 600 times lower than GR-{alpha} in the three groups. Coincubation 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-ß mRNA. GR-{alpha}, but not GR-ß, protein was detected at baseline and after cytokine exposure. Our data do not support the hypothesis that increased GR-ß expression can contribute to cytokine-induced glucocorticoid insensitivity.

Key Words: asthma • interleukin-2 • interleukin-4 • peripheral blood mononuclear cell




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