Prostaglandin E2-EP3 Signaling Induces Inflammatory Swelling by Mast Cell Activation

PGE(2) has long been known as a potentiator of acute inflammation, but its mechanisms of action still remain to be defined. In this study, we employed inflammatory swelling induced in mice by arachidonate and PGE(2) as models and dissected the role and mechanisms of action of each EP receptor at the molecular level. Arachidonate- or PGE(2)-induced vascular permeability was significantly reduced in EP3-deficient mice. Intriguingly, the PGE(2)-induced response was suppressed by histamine H-1 antagonist treatment, histidine decarboxylase deficiency, and mast cell deficiency. The impaired PGE(2)-induced response in mast cell-deficient mice was rescued upon reconstitution with wild-type mast cells but not with EP3-deficient mast cells. Although the number of mast cells, protease activity, and histamine contents in ear tissues in EP3-deficient mice were comparable to those in wild-type mice, the histamine contents in ear tissues were attenuated upon PGE(2) treatment in wild-type but not in EP3-deficient mice. Consistently, PGE(2)-EP3 signaling elicited histamine release in mouse peritoneal and bone marrow-derived mast cells, and it exerted degranulation and IL-6 production in a manner sensitive to pertussis toxin and a PI3K inhibitor and dependent on extracellular Ca2+ ions. These results demonstrate that PGE(2) triggers mast cell activation via an EP3-G(i/o)-Ca2+ influx/PI3K pathway, and this mechanism underlies PGE(2)-induced vascular permeability and consequent edema formation.