title: Distinct PGE2-responder and non-responder phenotypes in human mast cell populations: "all or nothing" enhancement of antigen-dependent mediator release.
abstract: Reports indicate that prostaglandin (PG)E(2) markedly enhances antigen-mediated degranulation in mouse bone marrow-derived mast cells (BMMCs) but not in human mast cells (HuMCs). We have examined the underlying mechanism(s) for this disparity in HuMCs derived from the peripheral blood of multiple donors in addition to mouse BMMCs. HuMCs from half of these donors failed to respond to PGE(2) and the PGE(2) EP3 receptor agonist, sulprostone. However, HuMCs from the remaining donors and the LAD2 human MC line responded to PGE(2) and sulprostone with marked enhancement of antigen-mediated degranulation and IL-8 production in a similar manner to that observed in mouse BMMCs. The EP2 agonist, butaprost, failed to modulate antigen-mediated responses in any type of MCs. These distinct phenotypes could not be explained by differences in EP2 or EP3 expression nor by differences in the ability of PGE(2) to elevate levels of cAMP, a signal recognized to down-regulate mast cell activation. Moreover, both responder and non-responder HuMC populations exhibited similar activation of phosphatidylinositol 3-kinase, and MAP kinases. However, translocation of PLCγ(1) to the cell membrane and the associated calcium signal were enhanced only in the responder HuMC population indicating that the link between EP3 and PLCγ is impaired in the non-responder HuMCs.
  
  
  CONCLUSIONS
  These data provide a cautionary note for the translating of observations in the mouse to human mast cell-dependent disorders, but may also provide a basis for examining the effects of co-activating receptors in patients susceptible to allergic conditions.
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1881, USA.
authors.forename: Hye Sun
authors.initials: HS
authors.lastname: Kuehn
authors.forename: Mi-Yeon
authors.initials: MY
authors.lastname: Jung
authors.forename: Michael A
authors.initials: MA
authors.lastname: Beaven
authors.forename: Dean D
authors.initials: DD
authors.lastname: Metcalfe
authors.forename: Alasdair M
authors.initials: AM
authors.lastname: Gilfillan
mesh_terms: D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015550:Cell Degranulation / Q000502:physiology*; D002460:Cell Line; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists / Q000378:metabolism*; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013045:Species Specificity
chemical_list: D016209:Interleukin-8; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; C016767:sulprostone; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D000527:Alprostadil; C048491:butaprost; D015232:Dinoprostone