Prostaglandin E2 selectively enhances the IgE-mediated production of IL-6 and granulocyte-macrophage colony-stimulating factor by mast cells through an EP1/EP3-dependent mechanism.
PGE(2) is an endogenously synthesized inflammatory mediator that is over-produced in chronic inflammatory disorders such as allergic asthma. In this study, we investigated the regulatory effects of PGE(2) on mast cell degranulation 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 specifically enhanced IL-6 production, and neither induced nor inhibited degranulation and the release of other mast cell cytokines, including IL-4, IL-10, IFN-gamma, 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 synergistically increased mast cell degranulation and IL-6 and GM-CSF, but not IL-4, production. A similar potentiation of degranulation and IL-6 production by PGE(2), in the context of IgE-directed activation, was observed in the well-established IL-3-dependent murine mast cell line, MC/9. RT-PCR analysis of unstimulated MC/9 cells revealed the expression of EP(1), EP(3), and EP(4) PGE receptor subtypes, including a novel splice variant of the EP(1) receptor. Pharmacological studies using PGE receptor subtype-selective analogs showed that the potentiation of IgE/Ag-induced degranulation and IL-6 production by PGE(2) is mediated through EP(1) and/or EP(3) receptors. Our results suggest that PGE(2) may profoundly alter the nature of the mast cell degranulation and cytokine responses at sites of allergic inflammation through an EP(1)/EP(3)-dependent mechanism.
Gomi
K
K
Departments of Microbiology and Immunology, and Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
Zhu
F G
FG
Marshall
J S
JS
D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D015550:Cell Degranulation / Q000276:immunology; D002460:Cell Line; D000242:Cyclic AMP / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D015232:Dinoprostone / Q000502:physiology*; D004357:Drug Synergism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D007073:Immunoglobulin E / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis*; D007700:Kinetics; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020033:Protein Isoforms / Q000096:biosynthesis / Q000502:physiology; D018078:Receptors, Prostaglandin E / Q000096:biosynthesis / Q000502:physiology*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D015290:Second Messenger Systems / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology; D001619:beta-N-Acetylhexosaminidases / Q000096:biosynthesis
D000276:Adjuvants, Immunologic; D016207:Cytokines; D015850:Interleukin-6; D020033:Protein Isoforms; C545636:Ptger1 protein, mouse; C545648:Ptger3 protein, mouse; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D007073:Immunoglobulin E; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000242:Cyclic AMP; D001619:beta-N-Acetylhexosaminidases; D015232:Dinoprostone