Effects of prostaglandin D2 and theophylline on rat serosal mast cells: discordance between increased cellular levels of cyclic AMP and activation of cyclic AMP-dependent protein kinase.

Abstract

Previous studies have shown that perturbation of the mast cell IgE-Fc receptor activates adenylate cyclase so as to raise cellular levels of cyclic AMP and to activate cyclic AMP-dependent protein kinase. Theophylline, an inhibitor of cytoplasmic cyclic nucleotide phosphodiesterase, raises cellular cyclic AMP levels, activates Type I and Type II cytoplasmic cyclic AMP-dependent protein kinase isoenzymes, and inhibits immunologic mediator release in a dose-dependent fashion. Since the EC50 values for each of these effects are similar (8 to 9.5 mM), it seems likely that a relationship exists between the activation of cyclic AMP-dependent protein kinase and the inhibition of mediator release. Such inhibition could be due to either to the uncovering of an inhibitory protein by phosphorylation or to the depletion of cyclic AMP-dependent protein kinase holoenzyme, which is essential for productive IgE-Fc receptor-induced activation-secretion coupling. PGD2, which also raises mast cell cyclic AMP levels in a dose-dependent fashion and interacts synergistically with theophylline in this regard, fails to suppress mediator release alone or to add to the inhibitory effect of theophylline. The finding that PGD2 also fails to activate cyclic AMP-dependent protein kinase suggests that the adenylate cyclase stimulated by this agonist is not linked to the mast cell activation-secretion response.