Anti-inflammatory activity of beta2-agonists in primary lung epithelial cells is independent of glucocorticoid receptor.
In patients with asthma and chronic obstructive pulmonary disease, the addition of long-acting beta(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). The present study investigates the effects of formoterol (FORM), salmeterol (SALM) and budesonide (BUD) on GR activation in bronchial epithelial cells via tumour necrosis factor-alpha-stimulated granulocyte-macrophage colony-stimulating factor (GM-CSF) release, GR nuclear translocation and GR-regulated reporter gene activity. Both BUD and FORM inhibited GM-CSF release by < or = 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 small interfering RNA-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 was not tested), in contrast to the clear effect of BUD. It was concluded that in bronchial epithelial cells, inhibition of granulocyte-macrophage colony-stimulating factor synthesis by formoterol and salmeterol does not act via previously demonstrated glucocorticoid receptor-related mechanisms, suggesting an alternative pathway in these cells.
Lovén
J
J
Department of Biological Sciences, AstraZeneca, 22187, Lund, Sweden.
Svitacheva
N
N
Jerre
A
A
Miller-Larsson
A
A
Korn
S H
SH
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy / Q000276:immunology; D015153:Blotting, Western; D001980:Bronchi / Q000187:drug effects / Q000276:immunology; D001993:Bronchodilator Agents / Q000494:pharmacology*; D019819:Budesonide / Q000494:pharmacology*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology; D004983:Ethanolamines / Q000494:pharmacology*; D000068759:Formoterol Fumarate; D017930:Genes, Reporter; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D000068299:Salmeterol Xinafoate; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D004983:Ethanolamines; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; D019819:Budesonide; D000068299:Salmeterol Xinafoate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000420:Albuterol; D000068759:Formoterol Fumarate