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

Aggregation of high affinity FcR for IgE (Fc epsilon RI) on mast cells acti vates intracellular signal transduction pathways, including the activation of protein tyrosine kinases, phosphatidylinositol 3-kinase (PI3-kinase), an d 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 PU-kinase. Although ligation of both receptors i nduces Pas and Raf-l activation, the downstream consequences of these early activation events are not well defined, except for the activation of extra cellular 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 extrac ellular signal-regulated kinases, SCF similarly activates all three MAP kin ases. 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-me diated JNK and p38 activation, but did not affect the activation of these k inases when stimulated through the SCFR. Wortmannin and cyclosporin A inhib ited FceRI-mediated production of TNF-alpha and IL-4 in addition to seroton in release in BMMC, These results indicate that both PI3-kinase and calcine urin may contribute to the regulation of cytokine gene transcription and th e degranulation response by modulating JNK activity in BMMC.