Abstract
Igs can be potent stimulants of eosinophil activation since interaction with IgA or IgG-coated particles can lead to eosinophil degranulation. We have investigated the comparative roles of mitogen-activated protein (MAP) kinases (MAPKs; ERK1/2 and p38) and phosphatidylinositol-3 kinase (PI3K) in the priming and regulation of Fc receptor functioning on human eosinophils utilizing a MAPK kinase (MEK) inhibitor (PD98059), a p38 inhibitor SB203580, and the widely used PI3K inhibitors wortmannin and LY294002. We demonstrate that priming of human eosinophils with Th2-derived cytokines, IL-4 and IL-5, differentially activate phosphotyrosine-associated PI3K and ERK and p38 MAP kinases. This activation can be inhibited by pre-incubation with wortmannin or LY294002, PD98059, and SB203580, respectively. Analysis of the effects of the inhibitors on rosette formation between human eosinophils and IgA- or IgG-coated beads revealed that activation of MEK was not required for IgA binding after priming with IL-4 or IL-5. However, inhibition of MEK did inhibit IL-5-primed binding of IgG-beads. The rosette formation of primed eosinophils with IgA-beads could be completely inhibited by wortmannin and LY294002 treatment, demonstrating a critical role for PI3K. Interestingly, inhibition of the p38 pathway also resulted in a complete blockade of IgA rosette formation. This work demonstrates regulatory control by inside-out signaling of Fc receptors by various cytokines on human eosinophils. Thus in vivo the local production of Th2-derived cytokines will regulate the effector functions of Fc receptors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Androstadienes / pharmacology
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Calcium-Calmodulin-Dependent Protein Kinases / physiology
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Chromones / pharmacology
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Eosinophils / drug effects*
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Eosinophils / immunology
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Flavonoids / pharmacology
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Humans
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Imidazoles / pharmacology
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Immunoglobulin A / immunology*
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Immunoglobulin G / immunology*
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Interleukin-4 / pharmacology*
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Interleukin-5 / pharmacology*
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Microspheres
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases*
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Morpholines / pharmacology
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Phosphatidylinositol 3-Kinases / physiology
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Protein Kinase Inhibitors
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Protein Kinases / physiology*
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Protein Processing, Post-Translational / drug effects
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Pyridines / pharmacology
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Receptors, Fc / drug effects*
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Receptors, Fc / immunology
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Receptors, IgG / drug effects*
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Receptors, IgG / immunology
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Rosette Formation
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Signal Transduction / physiology*
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Th2 Cells / metabolism
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Wortmannin
Substances
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Androstadienes
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Chromones
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Enzyme Inhibitors
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Flavonoids
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IgA receptor
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Imidazoles
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Immunoglobulin A
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Immunoglobulin G
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Interleukin-5
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Pyridines
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Receptors, Fc
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Receptors, IgG
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Interleukin-4
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Protein Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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SB 203580
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Wortmannin