By repressing inflammatory gene expression,
glucocorticoids are the most effective treatment for chronic inflammatory diseases such as
asthma. However, in some patients with severe disease, or who
smoke or suffer from
chronic obstructive pulmonary disease,
glucocorticoids are poorly effective. Although many investigators focus on defects in the repression of inflammatory gene expression,
glucocorticoids also induce (transactivate) the expression of numerous genes to elicit anti-inflammatory effects. Using human bronchial epithelial (BEAS-2B) and pulmonary (A549) cells, we show that
cytokines [
tumor necrosis factor α (TNFα) and
interleukin 1β],
mitogens [
fetal calf serum (FCS) and
phorbol ester], cigarette
smoke, and a G(q)-linked
G protein-coupled receptor agonist attenuate simple
glucocorticoid response element (GRE)-dependent transcription. With TNFα and FCS, this effect was not overcome by increasing concentrations of
dexamethasone,
budesonide, or
fluticasone propionate. Thus, the maximal ability of the
glucocorticoid to promote GRE-dependent transcription was reduced, and this was shown additionally for the
glucocorticoid-induced gene p57(KIP2). The long-acting β(2)-adrenoceptor agonists (LABAs)
formoterol fumarate and
salmeterol xinafoate enhanced simple GRE-dependent transcription to a level that could not be achieved by
glucocorticoid alone. In the presence of TNFα or FCS, which repressed
glucocorticoid responsiveness, these LABAs restored
glucocorticoid-dependent transcription to levels that were achieved by
glucocorticoid alone. Given the existence of genes, such as p57(KIP2), which may mediate anti-inflammatory actions of
glucocorticoids, we propose that repression of transactivation represents a mechanism for
glucocorticoid resistance and for understanding the clinical benefit of LABAs as an add-on
therapy in
asthma and
chronic obstructive pulmonary disease.