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 characterist ics of histamine release, and the pharmacologic properties. Objective: The role of cyclic 3',5'-adenosine monophosphate (cAMP) in chemi cal mediator release and cytokine production by human mast cells was determ ined. Methods: We investigated the effects of cAMP-elevating agents on IgE-mediat ed 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 his tamine, leukotrienes, and PGD2 (chemical mediators) and the production of G M-CSF, IL-5 and macrophage inflammatory protein-1 alpha (cytokines). Phosph odiesterase inhibitors (theophylline, rolipram, and cilostazol) had no effe ct on chemical mediators but suppressed cytokine production. Dibutyryl cAMP significantly suppressed both chemical mediator release and cytokine produ ction, suggesting that their induction was regulated by intracellular cAMP, Elevation of cAMP by beta-agonists at 10 minutes after treatment correlate d well with the inhibition of histamine release, There was a significant re lationship between cAMP elevation at 180 minutes and the inhibition of GM-C SF production at 360 minutes by beta-agonists, rolipram, or cilostazol. Alt hough 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, theophyllin e may inhibit GM-CSF production independently of cAMP.