Abstract
Mast cells, perhaps best known by their ability to trigger allergic reactions after stimulation through the FcepsilonRI, express the unusual phosphatidylinositol 3-kinase (PI3K)-dependent, Rac-binding protein SWAP-70. Here, we show that the IgE-mediated passive cutaneous and the systemic anaphylactic responses are strongly reduced in SWAP-70(-/-) mice. Cultured SWAP-70(-/-) immature bone marrow mast cells (BMMC) are also impaired in FcepsilonRI-mediated degranulation, which can be restored by expression of exogenous wild-type SWAP-70, but less so if a phosphatidylinositol trisphosphate (PIP(3)) binding mutant is expressed. SWAP-70 itself supports inositol-3-phosphate and PIP(3) production, the latter indicating a potential feedback from SWAP-70 towards PI3K. FcepsilonRI-stimulated transcription and release of cytokines is controlled by SWAP-70. Key FcepsilonRI signal transduction events like activation of LAT by phosphorylation, activation of Akt/PKB and of p38 MAP kinase are reduced in SWAP-70(-/-) BMMC, but ERK is strongly hyperactivated. Some requirements for SWAP-70 were apparent only under limited-strength signaling conditions. We suggest that SWAP-70 defines a new element of efficient mast cell activation upon FcepsilonRI signaling, important for the control of mast cell-dependent anaphylaxis.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Anaphylaxis / chemically induced
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Anaphylaxis / immunology*
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Anaphylaxis / metabolism
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Animals
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Cell Degranulation / physiology
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Cells, Cultured
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Cytokines / genetics
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Dinitrobenzenes / immunology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gene Expression
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Guanine Nucleotide Exchange Factors / genetics
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Guanine Nucleotide Exchange Factors / physiology*
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Immunoglobulin E / immunology
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Inositol 1,4,5-Trisphosphate / metabolism
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Interleukin-4 / blood
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Interleukin-4 / genetics
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Mast Cells / cytology
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Mast Cells / immunology
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Mast Cells / physiology*
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Mice
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Mice, Inbred Strains
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Mice, Knockout
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Minor Histocompatibility Antigens
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Models, Biological
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Nuclear Proteins / genetics
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Nuclear Proteins / physiology*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, IgE / immunology*
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Signal Transduction / immunology*
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Transfection
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Cytokines
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DNA-Binding Proteins
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Dinitrobenzenes
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Guanine Nucleotide Exchange Factors
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Minor Histocompatibility Antigens
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Nuclear Proteins
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Receptors, IgE
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Swap70 protein, mouse
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Interleukin-4
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Immunoglobulin E
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Inositol 1,4,5-Trisphosphate
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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p38 Mitogen-Activated Protein Kinases