FC-GAMMA-R-DEPENDENT MITOGEN-ACTIVATED PROTEIN-KINASE ACTIVATION IN LEUKOCYTES - A COMMON SIGNAL-TRANSDUCTION EVENT NECESSARY FOR EXPRESSION OF TNF-ALPHA AND EARLY ACTIVATION GENES

Cross-linking the receptors for the Fc domain of IgG (Fc gamma R) on l eukocytes induces activation of protein tyrosine kinases. The intermed iary molecules that transduce to the nucleus the signals leading to in duction of the diverse biological responses mediated by these receptor s are not clearly identified. We have investigated whether mitogen-act ivated protein kinases (MAPK) are involved in transmembrane signaling via the three Fc gamma R present on monocytic, polymer-phonuclear, and natural killer (NK) cells. Our results indicate that occupancy of Fc gamma RI and Fc gamma RII on the monocytic cell line THP-1 and on poly morphonuclear leukocytes (PMN) induces, transiently and with fast kine tics, MAPK phosphorylation, as indicated by decreased electrophoretic mobility in sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and increased amounts of the proteins in antiphosphotyrosine antibody immunoprecipitates. This, associated with increased enzymatic activit y, also occurs upon stimulation of the transmembrane isoform of CD16 ( Fc gamma RIIIA) in NK cells and in a T cell line expressing transfecte d Fc gamma RIIIA or ligand-binding chain in association with zeta, but not upon stimulation of the glycosil-phosphatidylinositol-anchored Fc gamma RIIIB on PMN. Using the specific MAP kinase kinase inhibitor PD 098059, we show that activation of MAPK is necessary for the Fc gamma R-dependent induction of c-fos and tumor necrosis factor alpha mRNA e xpression in monocytes and NK cells. These results underscore the role of MAPK as signal-transducing molecules controlling the expression of different genes relevant to leukocyte biology upon Fc gamma R stimula tion.