Prostaglandin E-2 selectively enhances the IgE-mediated production of IL-6and granulocyte-macrophage colony-stimulating factor by mast cells throughan EP1/EP3-dependent mechanism

PGE(2) is an endogenously synthesized inflammatory mediator that is over-pr oduced in chronic inflammatory disorders such as allergic asthma, In this s tudy, we investigated the regulatory effects of PGE(2) on mast cell degranu lation and the production of cytokines relevant to allergic disease. Murine bone marrow-derived mast cells (BMMC) were treated with PGE(2) alone or in the context of IgE-mediated activation. PGE(2) treatment alone specificall y enhanced IL-6 production, and neither induced nor inhibited degranulation and the release of other mast cell cytokines, including IL-4, IL-10, IFN-g amma, and GM-CSF, IgE/Ag-mediated activation of BMMC induced the secretion of IL-4, IL-6, and GM-CSF, and concurrent PGE(2) stimulation synergisticall y increased mast cell degranulation and IL-6 and GM-CSF, but not IL-4, prod uction. A similar potentiation of degranulation and IL-6 production by PGE( 2), in the context of IgE-directed activation, was observed in the well-est ablished IL-3-dependent murine mast cell line, MC/9. RT-PCR analysis of uns timulated MC/9 cells revealed the expression of EP1, EP3, and EP4 PGE recep tor subtypes, including a novel splice variant of the EP1 receptor. pharmac ological studies using PGE receptor subtype-selective analogs showed that t he potentiation of IgE/Ag-induced degranulation and IL-6 production by PGE( 2) is mediated through EP1 and/or EP3 receptors, Our results suggest that P GE(2) may profoundly alter the nature of the mast cell degranulation and cy tokine responses at sites of allergic inflammation through an EP1/EP3-depen dent mechanism.