COMMON AND DISTINCT SIGNALING PATHWAYS MEDIATE THE INDUCTION OF TNF-ALPHA AND IL-5 IN IGE PLUS ANTIGEN-STIMULATED MAST-CELLS

A small number of signaling cascades represented by mitogen-activated protein kinases, phosphoinositol-3-kinase, protein kinase C, signal tr ansducers and activators of transcription, Ca2+/calcineurin, and a few other molecules are linked to an incomparably large number of surface receptors. Parallel activation of several of these pathways and the e xistence of isozymes for a number of signal transmitting molecules gen erate the required complexity and specificity matching the receptor va riety. Here we show that the proinflammatory mediator TNF-alpha and th e growth factor IL-5 are activated along common and distinct signaling cascades in allergically stimulated murine mast cells. Both of them a re dependent on Ca2+ influx, activation of calcineurin and nuclear fac tor of activated T cells as well as a member of the atypical PKC famil y, most likely PKC mu. Additionally, mitogen-activated protein kinases for TNF-alpha and members of the classical or nonclassical PKCs for I L-5, respectively, were identified as additional required pathways. In hibition of the classical and nonclassical PKCs, however, does not abr ogate IL-5 induction but instead leads to a switch to mitogen-activate d protein kinases, which then become essential. The activated branches of this ''salvage'' signaling cascade are represented by extracellula r signal-regulated kinase 1/2 and c-jun NH2 terminal kinase 1 in aller gically stimulated mast cells.