Am. J. Respir. Crit. Care Med., Volume 162, Number 1, July 2000, 7-13

Glucocorticoid Receptor  and  in Glucocorticoid Dependent Asthma

ROSALIA GAGLIARDO, PASCAL CHANEZ, ANTONIO M. VIGNOLA, JEAN BOUSQUET, ISABELLE VACHIER, PHILIPPE GODARD, GIOVANNI BONSIGNORE, PASCAL DEMOLY, and MARC MATHIEU

Service des Maladies Respiratoires and Institut National de la Santé et de la Recherche Médicale U454, CHU de Montpellier, France; and Istituto di Fisiopatologia Respiratoria, Consiglio Nazionale delle Ricerche, Via Trabucco, Palermo, Italy

Patients with glucocorticoid (GC)-dependent asthma present an ongoing inflammation of the airways despite chronic long-term treatment with oral GC. Interleukin (IL)-8 and granulocyte/macrophage colony-stimulating factor (GM-CSF) have been implicated in airway inflammation in severe asthma and their synthesis is normally repressed by GC. To further characterize the inflammatory process in GC-dependent asthma, we measured the release of IL-8 and GM-CSF by peripheral blood mononuclear cells (PBMC) of eight normal subjects, six untreated controlled asthmatics, six untreated uncontrolled asthmatics, and nine GC-dependent asthmatics. We show that PBMC from GC-dependent asthmatics released high amounts of these cytokines despite chronic in vivo exposure to GC (p < 0.001 versus normal subjects). In contrast, when untreated uncontrolled asthmatics were given a short course of oral GC, IL-8 and GM-CSF production was inhibited (p = 0.0078). Release of IL-8 and GM-CSF by PBMC of GC-dependent asthmatics was reduced after in vitro GC treatment (p < 0.002). We investigated whether the incapacity of GC to inhibit production of these cytokines in vivo was the result of a dysregulation of the glucocorticoid receptor (GR) in GC-dependent asthma. GR and GR are, respectively, the functional receptor and a putative dominant negative form of the receptor. Western blot and polymerase chain reaction (PCR) analyses indicated that GR was expressed at similar level in all groups and was largely predominant over GR. Thus, persistent release of IL-8 and GM-CSF in GC-dependent asthma is not associated with low expression of GR or overexpression of GR.

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