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  • Title: Mitogen-activated protein kinase activation through Fc epsilon receptor I and stem cell factor receptor is differentially regulated by phosphatidylinositol 3-kinase and calcineurin in mouse bone marrow-derived mast cells.
    Author: Ishizuka T, Chayama K, Takeda K, Hamelmann E, Terada N, Keller GM, Johnson GL, Gelfand EW.
    Journal: J Immunol; 1999 Feb 15; 162(4):2087-94. PubMed ID: 9973482.
    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.
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