THE SYK PROTEIN-TYROSINE KINASE IS ESSENTIAL FOR FC-GAMMA RECEPTOR SIGNALING IN MACROPHAGES AND NEUTROPHILS

The cytoplasmic protein tyrosine kinase Syk has two amino-terminal SH2 domains that engage phosphorylated immunoreceptor tyrosine-based acti vation motifs in the signaling subunits of immunoreceptors. Syk, in co njunction with Src family kinases, has been implicated in immunorecept or signaling in both lymphoid and myeloid cells. We have investigated the role of Syk in Fc gamma receptor (Fc gamma R)-dependent and -indep endent responses in bone marrow-derived macrophages and neutrophils by using mouse radiation chimeras reconstituted with fetal liver cells f rom Syk(-/-) embryos. Chimeric mice developed an abdominal hemorrhage starting 2 to 3 months after transplantation that aas ultimately letha l. Syk-deficient neutrophils derived from the bone marrow were incapab le of generating reactive oxygen intermediates in response to Fc gamma R engagement but responded normally to tetradecanoyl phorbol acetate stimulation. Syk-deficient macrophages were defective in phagocytosis induced by Fc gamma R but showed normal phagocytosis in response to co mplement. The tyrosine phosphorylation of multiple cellular polypeptid es, including the Fc gamma R gamma chain, as well as Erk2 activation, was compromised in Syk(-/-) macrophages after Fc gamma R stimulation. In contrast, the induction of nitric oxide synthase in macrophages sti mulated with lipopolysaccharide and gamma interferon was not dependent on Syk Surprisingly, Syk-deficient macrophages were impaired in the a bility to survive or proliferate on plastic petri dishes. Taken togeth er, these results suggest that Syk has specific physiological roles in signaling from Fc gamma Rs in neutrophils and macrophages and raise t he possibility that in vivo, Syk is involved in signaling events other than those mediated by immunoreceptors.