Modulation of Stimulated Phospholipid Metabolism in Mast Cells by Pharmacologic Agents That Increase Cyclic 3′,5′ Adenosine Monophosphate Levels

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Abstract
Phospholipid (PL) metabolism is markedly stimulated during mediator release from isolated rat mast cells. The present studies were performed to extend studies of the association of these PL reactions with the mediator release process and to probe the mechanisms by which pharmacologic agents that increase cyclic 3′,5′ adenosine monophosphate (cAMP) levels inhibit mediator release. Theophylline (1 to 20 mM) and N6, O2-dibutyryl cAMP (DBcAMP, 1 to 10 mM) markedly inhibited 32PO4 incorporation into phosphatidic acid (PA), phosphatidylinositol (PI), and phosphatidylcholine (PC) in unstimulated mast cells. Epinephrine (1 to 100 µM) had no effect on PL labeling in resting cells. The histamine release and increased 32PO4 labeling of PA, PI, and PC observed in mast cells stimulated by a goat anti-rat IgE antiserum were inhibited in parallel by theophylline (ID50 approximately 5 mM for all parameters) and by DBcAMP (ID50 approximately 3 mM for all parameters). Epinephrine (1 to 100 µM) did not modify mediator release or labeling of PA or PC, but did modestly inhibit PI labeling (23% inhibition at 100 µM epinephrine). Theophylline (above 3 mM) was found to arrest significantly ongoing mediator release and PL labeling when added as late as 2 to 5 min after anti-IgE challenge. The parallel effects of these pharmacologic interventions on mediator release and PL metabolism provide further evidence that the two processes are biochemically linked.