Glucocorticoid receptor α and β in glucocorticoid dependent asthma

Patients with glucocorticoid (CC)-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 CM-CSF by peripheral blood mononuclear cells (PBMC) of eight normal subjects, six untreated controlled asthmatics, six untreated uncontrolled asthmatics, and nine CC-dependent asthmatics. We show that PBMC from CC-dependent asthmatics released high amounts of these cytokines despite chronic in vivo exposure to CC (p < 0.001 versus normal subjects). In contrast, when untreated uncontrolled asthmatics were given a short course of oral CC, IL-8 and CM-CSF production was inhibited (p = 0.0078). Release of IL-8 and GM-CSF by PBMC of CC-dependent asthmatics was reduced after in vitro GC treatment (p < 0.002). We investigated whether the incapacity of CC to inhibit production of these cytokines in vivo was the result of a dysregulation of the glucocorticoid receptor (GR) in CC-dependent asthma. GR alpha and GR beta 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 alpha was expressed at similar level in all groups and was largely predominant over GR beta. Thus, persistent release of IL-8 and CM-CSF in CC-dependent asthma is not associated with low expression of GR alpha or overexpression of GR beta.