Abstract
Activation of the high-affinity receptor for IgE, FcepsilonRI, is known to elicit its rapid down-regulation through internalization and degradation. In keeping with this, expression of all three FcepsilonRI subunits is decreased at the protein level after cross-linkage of IgE with antigen. However, we find that the FcepsilonRI beta-subunit is also selectively suppressed at the mRNA level, through a pathway primarily involving Fyn, Syk, PI3K, and NF-kappaB. IgG or calcium ionophore, stimuli known to mimic portions of the IgE signaling cascade, similarly suppressed beta-subunit expression. LPS, a NF-kappaB-activating TLR ligand, did not alter beta-subunit expression. As IgE increases FcepsilonRI expression, we examined the coordinated regulation of FcepsilonRI subunits during culture with IgE, followed by cross-linkage with antigen. IgE increased the expression of all three FcepsilonRI subunits and strikingly induced expression of the antagonistic beta(T). The ratio of beta:beta(T) protein expression decreased significantly during culture with IgE and was reset to starting levels by antigen cross-linkage. These changes in protein levels were matched by similar fluctuations in beta and beta(T) mRNAs. FcepsilonRIbeta is a key regulator of IgER expression and function, a gene in which polymorphisms correlate with allergic disease prevalence. The ability of IgE and FcepsilonRI signaling to coordinate expression of the beta and beta(T) subunits may comprise a homeostatic feedback loop-one that could promote chronic inflammation and allergic disease if dysregulated.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Gene Expression Regulation / genetics
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Gene Expression Regulation / immunology*
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Hypersensitivity / genetics
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Hypersensitivity / immunology
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Hypersensitivity / metabolism
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Immunoglobulin E / immunology*
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Immunoglobulin E / metabolism
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Immunoglobulin G / genetics
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Immunoglobulin G / immunology
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Immunoglobulin G / metabolism
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Immunologic Capping / genetics
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Immunologic Capping / immunology*
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / immunology
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Intracellular Signaling Peptides and Proteins / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Transgenic
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NF-kappa B / genetics
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NF-kappa B / immunology
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NF-kappa B / metabolism
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / immunology
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Phosphatidylinositol 3-Kinases / metabolism
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Polymorphism, Genetic / genetics
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Polymorphism, Genetic / immunology
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / immunology
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins c-fyn / genetics
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Proto-Oncogene Proteins c-fyn / immunology
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Proto-Oncogene Proteins c-fyn / metabolism
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Messenger / immunology
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Receptors, IgE / biosynthesis
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Receptors, IgE / genetics
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Receptors, IgE / immunology*
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Syk Kinase
Substances
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Immunoglobulin G
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Intracellular Signaling Peptides and Proteins
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NF-kappa B
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RNA, Messenger
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Receptors, IgE
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Immunoglobulin E
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Phosphatidylinositol 3-Kinases
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Protein-Tyrosine Kinases
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Fyn protein, mouse
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Proto-Oncogene Proteins c-fyn
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Syk Kinase
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Syk protein, mouse