Effects of prostaglandin E-2 and cAMP elevating drugs on GM-CSF release bycultured human airway smooth muscle cells - Relevance to asthma therapy

Human airway smooth muscle (HASM) cells release granulocyte macrophage-colo ny stimulating factor (CM-CSF) and express cyclooxygenase (COX)-2 (resultin g in the release of prostaglandin [PG] E-2) after stimulation with cytokine s, Because COX-2 activity can regulate a number of inflammatory processes, we have assessed its effects, as well as those of agents that modulate cycl ic adenosine monophosphate (cAMP), on CM-CSF release by HASM cells. Cells s timulated with a combination of proinflammatory cytokines (interleukin-lp a nd tumor necrosis factor-alpha each at 10 ng/ml) for 24 h released signific ant amounts of PGE(2) (measured by radioimmunoassay) and CM-CSF (measured b y enzyme-linked immunosorbent assay). Indomethacin and other COX-1/COX-2 in hibitors caused concentration-dependent inhibitions of PGE(2) concomitantly with increases in CM-CSF formation. Addition of exogenous PGE(2) or the be ta (2)-agonist fenoterol, which increase cAMP, to cytokine-treated HASM cel ls had no effect on GM-CSF release unless COX activity was first blocked wi th indomethacin. The type 4 phosphodiesterase inhibitors rolipram and SE 20 7499 both caused concentration-dependent reductions in CM-CSF production. T hus, when HASM cells are activated with cytokines they release PGE(2), whic h acts as a "braking mechanism" to limit the coproduction of CM-CSF, Moreov er, agents that elevate cAMP also reduce CM-CSF formation by these cells.