In diseases such as asthma, airways smooth muscle (ASM) cells play a synthetic role by secreting inflammatory mediators such as GM-CSF, IL-6 or IL-8, and by expressing surface adhesion molecules including ICAM-1. In the current study, PGE₂, forskolin, and both short-acting (salbutamol) and long- acting (salmeterol and formoterol) ₂-adrenoceptor agonists reduced the expression of ICAM-1 and the release of GM-CSF evoked by IL-1 in ASM cells. IL-1-induced IL-8 release was also repressed by both PGE₂ and forskolin, whereas the ₂-adrenoceptor agonists were ineffective. In each case, the repression of these inflammatory indices was prevented by adenoviral over-expression of PKI, a highly selective PKA inhibitor. These data indicate a PKA-dependent mechanism of repression and suggest that agents, which 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-B-dependent genes, we examined the effects of forskolin and the ₂-adrenoceptor agonists on NF-B activation, using an adenoviral-delivered NF-B-dependent luciferase reporter. There was no effect on luciferase activity measured in the presence of either forskolin or ₂-adrenoceptor agonists. This finding is consistent with the observation that IL-1-induced expression of IL-6, a known NF-B-dependent gene in ASM, was also unaffected by ₂-adrenoceptor agonists, forskolin, PGE₂, 8Br-cAMP or rolipram. Collectively, hese results indicate that the repression of IL-1-induced repression of ICAM-1 expression and GM-CSF release by cAMP-elevating agents including ₂-adrenoceptor agonists may not occur through a generic effect on NF-B.