title: Prostaglandin E2-EP3 signaling induces inflammatory swelling by mast cell activation.
abstract: PGE2 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 PGE2 as models and dissected the role and mechanisms of action of each EP receptor at the molecular level. Arachidonate- or PGE2-induced vascular permeability was significantly reduced in EP3-deficient mice. Intriguingly, the PGE2-induced response was suppressed by histamine H1 antagonist treatment, histidine decarboxylase deficiency, and mast cell deficiency. The impaired PGE2-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 PGE2 treatment in wild-type but not in EP3-deficient mice. Consistently, PGE2-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 Ca(2+) ions. These results demonstrate that PGE2 triggers mast cell activation via an EP3-Gi/o-Ca(2+) influx/PI3K pathway, and this mechanism underlies PGE2-induced vascular permeability and consequent edema formation.
authors.affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan;
authors.forename: Kazushi
authors.initials: K
authors.lastname: Morimoto
authors.forename: Naritoshi
authors.initials: N
authors.lastname: Shirata
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Taketomi
authors.forename: Soken
authors.initials: S
authors.lastname: Tsuchiya
authors.forename: Eri
authors.initials: E
authors.lastname: Segi-Nishida
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Inazumi
authors.forename: Kenji
authors.initials: K
authors.lastname: Kabashima
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tanaka
authors.forename: Makoto
authors.initials: M
authors.lastname: Murakami
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sugimoto
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000633:toxicity; D002118:Calcium / Q000502:physiology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D015550:Cell Degranulation; D015232:Dinoprostone / Q000502:physiology*; D004487:Edema / Q000209:etiology / Q000503:physiopathology*; D006636:Histamine Release / Q000187:drug effects; D007249:Inflammation / Q000150:complications / Q000503:physiopathology*; D015850:Interleukin-6 / Q000502:physiology; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018375:Neutrophil Activation; D009195:Peroxidase / Q000032:analysis; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013047:Specific Pathogen-Free Organisms
chemical_list: D016718:Arachidonic Acid; D002118:Calcium; D015232:Dinoprostone; D015850:Interleukin-6; D009195:Peroxidase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D058308:Receptors, Prostaglandin E, EP3 Subtype; C545648:Ptger3 protein, mouse; C577686:interleukin-6, mouse