title: Human mast cells express multiple EP receptors for prostaglandin E2 that differentially modulate activation responses.
abstract: Prostaglandin E2 (PGE2) blocks mast-cell (MC)-dependent allergic responses in humans but activates MCs in vitro. We assessed the functions of the EP receptors for PGE2 on cultured human MCs (hMCs). hMCs expressed the EP3, EP2, and EP4 receptors. PGE2 stimulated the accumulation of cyclic adenosine monophosphate (cAMP), and suppressed both Fc epsilonRI-mediated eicosanoid production and tumor necrosis factor-alpha (TNF-alpha) generation. PGE2 also caused phosphorylation of extracellular signal-regulated kinase (ERK), exocytosis, and production of prostaglandin D2 (PGD2), as well as leukotriene C4 (LTC4) when protein kinase A (PKA) was inhibited. An EP3 receptor-selective agonist, AE-248, mimicked PGE2-mediated ERK phosphorylation, exocytosis, and eicosanoid formation. Selective agonists of both EP2 and EP4 receptors (AE1-259-01 and AE-329, respectively) stimulated cAMP accumulation. No selective agonist, alone or in combination, was as effective as PGE2. AE-248, AE1-259-01, and AE-329 all inhibited Fc epsilonRI-mediated TNF-alpha generation, while AE1-259-01 blocked eicosanoid production. PGE2 caused the expression of inducible cAMP early repressor (ICER) by a pathway involving PKA and ERK. Thus, while PGE2 activates MCs through EP3 receptors, it also counteracts Fc epsilonRI-mediated eicosanoid production through EP2 receptors and PKA, and blocks cytokine transcription. These functions explain the potency of PGE2 as a suppressor of early- and late-phase allergic responses.
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Chunli
authors.initials: C
authors.lastname: Feng
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Beller
authors.forename: Savita
authors.initials: S
authors.lastname: Bagga
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Boyce
mesh_terms: D002478:Cells, Cultured; D000242:Cyclic AMP / Q000276:immunology / Q000378:metabolism; D051786:Cyclic AMP Response Element Modulator / Q000096:biosynthesis / Q000276:immunology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000276:immunology / Q000378:metabolism; D015232:Dinoprostone / Q000276:immunology* / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D017997:Leukotriene C4 / Q000096:biosynthesis / Q000276:immunology; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000276:immunology; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000096:biosynthesis / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
chemical_list: C497410:CREM protein, human; C034102:FcRI protein, human; D047908:Intracellular Signaling Peptides and Proteins; D018078:Receptors, Prostaglandin E; D014409:Tumor Necrosis Factor-alpha; D051786:Cyclic AMP Response Element Modulator; D017997:Leukotriene C4; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D015232:Dinoprostone