title: Early divergence of Fc epsilon receptor I signals for receptor up-regulation and internalization from degranulation, cytokine production, and survival.
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.
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
authors.forename: Jiro
authors.initials: J
authors.lastname: Kitaura
authors.forename: Wenbin
authors.initials: W
authors.lastname: Xiao
authors.forename: Mari
authors.initials: M
authors.lastname: Maeda-Yamamoto
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kawakami
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology*; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D004140:Dinitrophenols / Q000494:pharmacology; D004306:Dose-Response Relationship, Immunologic; D004792:Enzyme Precursors / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D006241:Haptens / Q000494:pharmacology; D007073:Immunoglobulin E / Q000276:immunology / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D008407:Mast Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D017455:Receptors, IgE / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D000072377:Syk Kinase; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D019061:src-Family Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology
chemical_list: D000888:Antibodies, Anti-Idiotypic; D016207:Cytokines; D004140:Dinitrophenols; D004792:Enzyme Precursors; D006241:Haptens; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D017455:Receptors, IgE; C026408:anti-IgE antibodies; C034638:dinitrophenyl-bovine serum albumin; D012710:Serum Albumin, Bovine; D007073:Immunoglobulin E; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases