Comparison of FcϵRI- and FcγRI-mediated degranulation and TNF-α synthesis in human mast cells: selective utilization of phosphatidylinositol-3-kinase for FcγRI-induced degranulation

Abstract

We have demonstrated that CD34⁺ IFN-γ-treated human mast cells (HuMC) express functional FcγRI and that aggregation of these receptors leads to mediator release. As the signaling pathways linking FcγRI aggregation to mediator release are unknown, we examined FcγRI-dependent activation of specific signal transduction molecules and determined the relative involvement of these events in HuMC degranulation and TNF-α production following both FcγRI and FcϵRI aggregation. FcγRI aggregation resulted in the phosphorylation/activation of srckinases and p72^syk and subsequent tyrosine phosphorylation of multiple substrates. Inhibitor studies revealed that these responses were required for degranulation and TNF-α synthesis. Both FcγRI and FcϵRI aggregation also activated the MAP kinases ERK 1/2, JNK and p38 and this was necessary for TNF-α synthesis, but not degranulation for both receptors. Thus, signalingevents in HuMC following aggregation of FcγRI were generally similar to those observed following FcϵRI aggregation. The one exception was that, although phosphatidylinositol-3-kinase was activated after both FcϵRI and FcγRI aggregation, only the FcγRI appeared to require this molecule for degranulation.