Role of cyclic 3′,5′-adenosine monophosphate in the regulation of chemical mediator release and cytokine production from cultured human mast cells

Background: Cultured human mast cells are known to resemble human lung mast cells in terms of the profiles of intracellular protease, the characteristics of histamine release, and the pharmacologic properties. Objective: The role of cyclic 3',5'-adenosine monophosphate (cAMP) in chemical mediator release and cytokine production by human mast cells was determined. Methods: We investigated the effects of cAMP-elevating agents on IgE-mediated chemical mediator release and cytokine production by cultured human mast cells. We also examined the relationship between intracellular cAMP levels and the inhibition of chemical mediator release or cytokine production by various drugs. Results: beta-agonists significantly suppressed IgE-mediated release of histamine, leukotrienes, and PGD2 (chemical mediators) and the production of GM-CSF, IL-5 and macrophage inflammatory protein-1 alpha (cytokines). Phosphodiesterase inhibitors (theophylline, rolipram, and cilostazol) had no effect on chemical mediators but suppressed cytokine production. Dibutyryl cAMP significantly suppressed both chemical mediator release and cytokine production, suggesting that their induction was regulated by intracellular cAMP, Elevation of cAMP by beta-agonists at 10 minutes after treatment correlated well with the inhibition of histamine release, There was a significant relationship between cAMP elevation at 180 minutes and the inhibition of GM-CSF production at 360 minutes by beta-agonists, rolipram, or cilostazol. Although 100 mu mol/L theophylline significantly inhibited GM-CSF production, it had no effect on cAMP. Conclusion: Elevation of cAMP may be responsible for the inhibitory effect of beta-agonists, rolipram, and cilostazol on chemical mediator release and cytokine production by cultured human mast cells. In contrast, theophylline may inhibit GM-CSF production independently of cAMP.