1. Early divergence of Fc epsilon receptor I signals for receptor up-regulation and internalization from degranulation, cytokine production, and survival.
- Author
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Kitaura J, Xiao W, Maeda-Yamamoto M, Kawakami Y, Lowell CA, and Kawakami T
- Subjects
- Animals, Antibodies, Anti-Idiotypic pharmacology, Bone Marrow Cells cytology, Bone Marrow Cells immunology, Bone Marrow Cells metabolism, Cell Degranulation genetics, Cell Survival genetics, Cell Survival immunology, Cells, Cultured, Dinitrophenols pharmacology, Dose-Response Relationship, Immunologic, Enzyme Precursors deficiency, Enzyme Precursors genetics, Enzyme Precursors physiology, Haptens pharmacology, Immunoglobulin E immunology, Immunoglobulin E pharmacology, Interleukin-6 biosynthesis, Intracellular Signaling Peptides and Proteins, Kinetics, Mast Cells cytology, Mice, Mice, Inbred C57BL, Mice, Knockout, Protein-Tyrosine Kinases deficiency, Protein-Tyrosine Kinases genetics, Protein-Tyrosine Kinases physiology, Receptors, IgE biosynthesis, Receptors, IgE metabolism, Serum Albumin, Bovine pharmacology, Signal Transduction genetics, Syk Kinase, Up-Regulation genetics, src-Family Kinases deficiency, src-Family Kinases genetics, src-Family Kinases physiology, Cell Degranulation immunology, Cytokines biosynthesis, Mast Cells immunology, Mast Cells metabolism, Receptors, IgE physiology, Signal Transduction immunology, Up-Regulation immunology
- Abstract
Mast cells play a critical role in IgE-dependent immediate hypersensitivity. Monomeric IgE binding to its high affinity receptor (FcepsilonRI) results in a number of biological outcomes in mouse mast cells, including increased surface expression of FcepsilonRI and enhanced survival. IgE molecules display heterogeneity in inducing cytokine production; highly cytokinergic IgEs cause extensive FcepsilonRI aggregation, leading to potent enhancement of survival and other activation events, whereas poorly cytokinergic IgEs can do so less efficiently. In this study, we demonstrate that IgE-induced receptor up-regulation is not sensitive to monovalent hapten, which can prevent receptor aggregation induced by IgE, whereas other activation events such as receptor internalization, degranulation, IL-6 production, and survival are sensitive to monovalent hapten. IgE-induced receptor up-regulation is also unique in that no Src family kinases, Syk, or Btk are required for it. By contrast, highly cytokinergic IgE-induced receptor internalization is dependent on Lyn, but not other Src family kinases, Syk, or Btk, whereas degranulation, IL-6 production, and survival require Syk. Weak to moderate stimulation with IgE plus anti-IgE or IgE plus Ag enhances survival, while stronger signals are required for degranulation and IL-6 production. Collectively, signals emanated from IgE-bound FcepsilonRI for receptor up-regulation and internalization are shown to diverge at the receptor or receptor-proximal levels from those for other biological outcomes.
- Published
- 2004
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