GLUCOCORTICOID REGULATION OF GM-CSF - EVIDENCE FOR TRANSCRIPTIONAL MECHANISMS IN AIRWAY EPITHELIAL-CELLS

Inflammation plays a central role in the pathogenesis of asthma. Gluco corticoids are first-line anti-inflammatory therapy in the treatment o f asthma and are effective inhibitors of inflammatory cytokines. Clini cal data demonstrate that granulocyte-macrophage colony-stimulating fa ctor (GM-CSF) production by airway epithelial cells may be an importan t target of inhaled glucocorticoid therapy. We examined the regulatory mechanisms of GMCSF expression by interleukin-1 beta (IL-1 beta) and the synthetic glucocorticoid dexamethasone in the BEAS-2B human bronch ial epithelial cell line. IL-1 beta stimulation resulted in a 15-fold induction of GM-CSF protein, which was associated with a corresponding 47-fold maximal induction of GM-CSF mRNA levels. Treatment with the t ranscriptional inhibitor actinomycin D before IL-1 beta stimulation co mpletely abolished induction of GM-CSF mRNA, whereas incubation with c ycloheximide had no effect. Taken together, these data demonstrate tha t IL-1 beta induction of GM-CSF is mediated through transcriptional me chanisms. Dexamethasone treatment of BEAS-2B cells produced an 80% inh ibition of IL-1 beta-induced GM-CSF protein and a 51% inhibition of GM -CSF mRNA. GM-CSF mRNA was rapidly degraded in these cells, and dexame thasone treatment did not significantly affect this decay rate. We con clude that, in the BEAS-2B bronchial epithelial cell line, IL-1 beta i nduction and dexamethasone repression of GM-CSF expression are mediate d predominantly through transcriptional mechanisms.