Effect of β₂-adrenoceptor agonists and other cAMP-elevating agents on inflammatory gene expression in human ASM cells: a role for protein kinase A

In diseases such as asthma, airway smooth muscle (ASM) cells play a synthetic role by secreting inflammatory mediators such as granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, or IL-8 and by expressing surface adhesion molecules, including ICAM-1. In the present study, PGE 2 , forskolin, and short-acting (salbutamol) and long-acting (salmeterol and formoterol) β 2 -adrenoceptor agonists reduced the expression of ICAM-1 and the release of GM-CSF evoked by IL-1β in ASM cells. IL-1β-induced IL-8 release was also repressed by PGE 2 and forskolin, whereas the β 2 -adrenoceptor agonists were ineffective. In each case, repression of these inflammatory indexes was prevented by adenoviral overexpression of PKIα, a highly selective PKA inhibitor. These data indicate a PKA-dependent mechanism of repression and suggest that agents that elevate intracellular cAMP, and thereby activate PKA, may have a widespread anti-inflammatory effect in ASM cells. Since ICAM-1 and GM-CSF are highly NF-κB-dependent genes, we used an adenoviral-delivered NF-κB-dependent luciferase reporter to examine the effects of forskolin and the β 2 -adrenoceptor agonists on NF-κB activation. There was no effect on luciferase activity measured in the presence of forskolin or β 2 -adrenoceptor agonists. This finding is consistent with the observation that IL-1β-induced expression of IL-6, a known NF-κB-dependent gene in ASM, was also unaffected by β 2 -adrenoceptor agonists, forskolin, PGE 2 , 8-bromo-cAMP, or rolipram. Collectively, these results indicate that repression of IL-1β-induced ICAM-1 expression and GM-CSF release by cAMP-elevating agents, including β 2 -adrenoceptor agonists, may not occur through a generic effect on NF-κB.