Anti-inflammatory activity of ₂-agonists in primary lung epithelial cells is independent of GR

¹ Dept of Biological Sciences, AstraZeneca R&D Lund, Lund, Sweden

^* To whom correspondence should be addressed. E-mail: Solange.Korn{at}astrazeneca.com.

	Abstract

In patients with asthma and chronic obstructive pulmonary disease, the addition of long acting ₂-agonists (LABA) to glucocorticosteroids (GCS) results in better control than increasing the dose of GCS alone. In smooth muscle cells and fibroblasts, one apparent underlying mechanism involves the ability of LABAs to activate the glucocorticoid receptor (GR).

We investigated the effects of FORM, salmeterol (SALM) and BUD on GR activation in bronchial epithelial cells via TNF-stimulated GM-CSF release, GR nuclear translocation, and GR regulated reporter gene activity.

Both BUD and FORM inhibited GM-CSF release up to 50%. The combination of these two drugs, in clinically relevant concentrations, inhibited GM-CSF release by 85% down to unstimulated levels. A similar inhibition was obtained when combining BUD and SALM. The ability of FORM to inhibit GM-CSF synthesis was not altered by siRNA-mediated depletion of GR and FORM nor SALM induced GR translocation into the cell nucleus. In addition, FORM did not activate GR regulated reporter gene activity (SALM not tested), in contrast to the clear effect of BUD. It was concluded that, in bronchial epithelial cells, inhibition of GM-CSF synthesis by FORM and SALM does not act via previously demonstrated GR-related mechanisms, suggesting an alternative pathway in these cells.