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, PGE2, forskolin, and short- acting (salbutamol) and long-acting (salmeterol and formoterol) beta(2)-adrenoceptor agonists reduced the expression of ICAM-1 and the release of GM-CSF evoked by IL-1 beta in ASM cells. IL-1 beta-induced IL-8 release was also repressed by PGE2 and forskolin, whereas the beta(2)-adrenoceptor agonists were ineffective. In each case, repression of these inflammatory indexes was prevented by adenoviral overexpression of PKI alpha, 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-kappa B-dependent genes, we used an adenoviral-delivered NF-kappa B-dependent luciferase reporter to examine the effects of forskolin and the beta(2)-adrenoceptor agonists on NF-kappa B activation. There was no effect on luciferase activity measured in the presence of forskolin or beta(2)-adrenoceptor agonists. This finding is consistent with the observation that IL-1 beta-induced expression of IL-6, a known NF-kappa B-dependent gene in ASM, was also unaffected by beta(2)-adrenoceptor agonists, forskolin, PGE2, 8-bromo-cAMP, or rolipram. Collectively, these results indicate that repression of IL-1 beta-induced ICAM-1 expression and GM-CSF release by cAMP-elevating agents, including beta(2)-adrenoceptor agonists, may not occur through a generic effect on NF-kappa B.