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Modulation of Stimulated Phospholipid Metabolism in Mast Cells by Pharmacologic Agents That Increase Cyclic 3',5' Adenosine Monophosphate Levels¹

Washington University School of Medicine, Department of Internal Medicine, Division of Allergy and Immunology, Howard Hughes Medical Institute Laboratory, 660 South Euclid Avenue, St. Louis, Missouri 63110

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.

Footnotes

¹ This work was supported by National Institutes of Health Grants 1 R01 AI 13380 and 1 P01 AI 12450.

² Donald Kennerly is supported by the Medical Scientist Training Program (5T32 GMO 7200).

³ Timothy Sullivan is supported by United Public Health Service Grant 1 K07 AI 00190.