title: The role of SHIP in the development and activation of mouse mucosal and connective tissue mast cells.
abstract: Although SHIP is a well-established suppressor of IgE plus Ag-induced degranulation and cytokine production in bone marrow-derived mast cells (BMMCs), little is known about its role in connective tissue (CTMCs) or mucosal (MMCs) mast cells. In this study, we compared SHIP's role in the development as well as the IgE plus Ag and TLR-induced activation of CTMCs, MMCs, and BMMCs and found that SHIP delays the maturation of all three mast cell subsets and, surprisingly, that it is a positive regulator of IgE-induced BMMC survival. We also found that SHIP represses IgE plus Ag-induced degranulation of all three mast cell subsets and that TLR agonists do not trigger their degranulation, whether SHIP is present or not, nor do they enhance IgE plus Ag-induced degranulation. In terms of cytokine production, we found that in MMCs and BMMCs, which are poor producers of TLR-induced cytokines, SHIP is a potent negative regulator of IgE plus Ag-induced IL-6 and TNF-α production. Surprisingly, however, in splenic or peritoneal derived CTMCs, which are poor producers of IgE plus Ag-induced cytokines, SHIP is a potent positive regulator of TLR-induced cytokine production. Lastly, cell signaling and cytokine production studies with and without LY294002, wortmannin, and PI3Kα inhibitor-2, as well as with PI3K p85α(-/-) BMMCs and CTMCs, are consistent with SHIP positively regulating TLR-induced cytokine production via an adaptor-mediated pathway while negatively regulating IgE plus Ag-induced cytokine production by repressing the PI3K pathway.
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Jens
authors.initials: J
authors.lastname: Ruschmann
authors.forename: Frann
authors.initials: F
authors.lastname: Antignano
authors.forename: Vivian
authors.initials: V
authors.lastname: Lam
authors.forename: Kim
authors.initials: K
authors.lastname: Snyder
authors.forename: Connie
authors.initials: C
authors.lastname: Kim
authors.forename: Martha
authors.initials: M
authors.lastname: Essak
authors.forename: Angela
authors.initials: A
authors.lastname: Zhang
authors.forename: Ann Hsu-An
authors.initials: AH
authors.lastname: Lin
authors.forename: Raghuveer Singh
authors.initials: RS
authors.lastname: Mali
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
authors.forename: Gerald
authors.initials: G
authors.lastname: Krystal
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D015550:Cell Degranulation / Q000276:immunology; D002454:Cell Differentiation; D019070:Cell Lineage / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D007073:Immunoglobulin E / Q000276:immunology*; D000072181:Inositol Polyphosphate 5-Phosphatases; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D008407:Mast Cells / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000166:cytology / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
chemical_list: D000941:Antigens; D007073:Immunoglobulin E; D000072181:Inositol Polyphosphate 5-Phosphatases; D015850:Interleukin-6; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha