Receptors and signaling mechanisms required for prostaglandin E2-mediated regulation of mast cell degranulation and IL-6 production

Mast cells are implicated in the pathogenesis of a broad spectrum of immunological disorders. These cells release inflammatory mediators in response to a number of stimuli, including IgE-Ag complexes. The degranulation of mast cells is modified by PGs. To begin to delineate the pathway(s) used by PGs to regulate mast cell function, we examined bone marrow-derived mast cells (BMMC) cultured from mice deficient in the EP1, EP2, EP3, and EP4 receptors for PGE(2). Although BMMCs express all four of these PGE(2) receptors, potentiation of Ag-stimulated degranulation and IL-6 cytokine production by PGE(2) is dependent on the EP3 receptor. Consistent with the coupling of this receptor to G(alphai), PGE(2) activation of the EP3 receptor leads to both inhibition of adenylate cyclase and increased intracellular Ca2+. The magnitude of increase in intracellular Ca2+ induced by EP3 activation is similar to that observed after activation of cells with IgE and Ag. Although PGE alone is not sufficient to initiate BMMC degranulation, stimulation of cells with PGE along with PMA induces degranulation. These actions are mediated by the EP3 receptor through signals involving Ca2+ mobilization and/or decreased CAMP levels. Accordingly, these studies identify PGE(2)/EP3 as a proinflammatory signaling pathway that promotes mast cell activation.