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* Department of Medicine and
Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599;
Department of Medicine, Division of Nephrology, Duke University, and Durham Veterans Affairs Medical Centers, Durham, NC 27710;
Genetic Technologies, Pfizer Global Research and Development, Groton, CT 06340; and
¶ Institut National de la Santé et de la Recherche Médicale, Institut Pasteur de Lille, Lille, France
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 PGE2. Although BMMCs express
all four of these PGE2 receptors, potentiation of
Ag-stimulated degranulation and IL-6 cytokine production by
PGE2 is dependent on the EP3 receptor.
Consistent with the coupling of this receptor to G
i,
PGE2 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 PGE2/EP3 as
a proinflammatory signaling pathway that promotes mast cell
activation.
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