Abstract
Aggregation of high affinity FcR for IgE (Fc epsilon RI) on mast cells activates intracellular signal transduction pathways, including the activation of protein tyrosine kinases, phosphatidylinositol 3-kinase (PI3-kinase), and protein kinase C. Binding of stem cell factor (SCF) to its receptor (SCFR, c-Kit) on mast cells also induces increases in intrinsic tyrosine kinase activity and activation of PI3-kinase. Although ligation of both receptors induces Ras and Raf-1 activation, the downstream consequences of these early activation events are not well defined, except for the activation of extracellular signal-regulated kinases (ERK). Addition of Ag (OVA) to mouse bone marrow-derived mast cells (BMMC) sensitized with anti-OVA IgE triggers the activation of three members of the mitogen-activated protein (MAP) kinase family, c-Jun amino-terminal kinase (JNK), p38 MAP kinase (p38), and extracellular signal-regulated kinases. SCF similarly activates all three MAP kinases. Wortmannin, an inhibitor of PI3-kinase, inhibited both Fc epsilon RI- and SCFR-mediated JNK activation and partially inhibited Fc epsilon RI, but not SCFR-mediated p38 activation. Cyclosporin A inhibited Fc epsilon RI-mediated JNK and p38 activation, but did not affect the activation of these kinases when stimulated through the SCFR. Wortmannin and cyclosporin A inhibited Fc epsilon RI-mediated production of TNF-alpha and IL-4 in addition to serotonin release in BMMC. These results indicate that both PI3-kinase and calcineurin may contribute to the regulation of cytokine gene transcription and the degranulation response by modulating JNK activity in BMMC.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Androstadienes / pharmacology
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Animals
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Bone Marrow Cells / drug effects
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Bone Marrow Cells / enzymology*
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Bone Marrow Cells / metabolism
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Calcineurin / physiology*
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cyclosporine / pharmacology
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Enzyme Activation / drug effects
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Female
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Flavonoids / pharmacology
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Interleukin-4 / antagonists & inhibitors
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Interleukin-4 / biosynthesis
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JNK Mitogen-Activated Protein Kinases
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Mast Cells / drug effects
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Mast Cells / enzymology*
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Mast Cells / metabolism
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Mice
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Mice, Inbred BALB C
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinases*
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Molecular Sequence Data
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Phosphatidylinositol 3-Kinases / physiology*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-kit / metabolism
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Proto-Oncogene Proteins c-kit / physiology*
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Proto-Oncogene Proteins*
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Receptor Aggregation / drug effects
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Receptors, IgE / metabolism
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Receptors, IgE / physiology*
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Serotonin / metabolism
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Serotonin Antagonists / pharmacology
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / biosynthesis
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Wortmannin
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p38 Mitogen-Activated Protein Kinases
Substances
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Androstadienes
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Flavonoids
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Proto-Oncogene Proteins
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Receptors, IgE
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Serotonin Antagonists
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Tumor Necrosis Factor-alpha
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Interleukin-4
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Serotonin
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Cyclosporine
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Proto-Oncogene Proteins c-kit
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Calcineurin
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Wortmannin