SWAP-70 regulates mast cell FcepsilonRI-mediated signaling and anaphylaxis.
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.
Sivalenka
Raja R
RR
Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY, USA.
Sinha
Manoj
M
Jessberger
Rolf
R
D000707:Anaphylaxis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D015550:Cell Degranulation / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004136:Dinitrobenzenes / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000502:physiology*; D007073:Immunoglobulin E / Q000276:immunology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D015847:Interleukin-4 / Q000097:blood / Q000235:genetics; D008407:Mast Cells / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017455:Receptors, IgE / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D004268:DNA-Binding Proteins; D004136:Dinitrobenzenes; D020662:Guanine Nucleotide Exchange Factors; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; D017455:Receptors, IgE; C113365:Swap70 protein, mouse; D015847:Interleukin-4; D007073:Immunoglobulin E; D015544:Inositol 1,4,5-Trisphosphate; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases