Human type 1 Fc receptors (FcRI) bind with high affinity (K = 10M) Fc regions of monomeric IgG1 and IgG3. As demonstrated in this report, interaction of IgG-Fc with the ligand binding site on FcRI alters its capacity for aggregation-dependent signaling. This Fc-dependence was demonstrated in normal monocytes and U937-10.6 cells exposed to monomeric IgG and then to anti-FcRI F(ab`) that cross-link the receptor. Using O production to measure cell signaling, we found that binding by high affinity IgGs of various species, as well as by murine hybrid IgGs containing only one high affinity heavy chain, resulted in a marked increase in FcRI-mediated signaling. Preaggregated FcRI/IgG had a ratio of one. IgG binding after aggregation of unligated FcRI did not restore signaling. Dose responses indicated that concentrations of IgG that saturated FcRI optimized transductional activity. The inclusion of unligated with ligated FcRI in aggregates depressed activity, indicating a lack of trans-activation of unligated FcRI. Significantly, IgG-binding markedly increased aggregation-dependent tyrosine phosphorylation of FcRI -chains and the association of tyrosine phosphorylated Syk. Thus, the consequences of IgG-Fc binding were increases in aggregation-dependent phosphorylation of FcRI -chains, recruitment of pp72Syk to FcRI, and signaling of the NADPH oxidase pathway.

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