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

We have demonstrated that CD34(+) IFN-gamma-treated human mast cells (HuMC) express functional FcgammaRI and that aggregation of these receptors leads to mediator release. As the signaling pathways linking FcgammaRI aggregation to mediator release are unknown, we examined FcgammaRI-dependent activation of specific signal transduction molecules and determined the relative involvement of these events in HuMC degranulation and TNF-alpha production following both FcgammaRI and FcepsilonRI aggregation. FcgammaRI aggregation resulted in the phosphorylation/activation of src kinases and P72(syk) and subsequent tyrosine phosphorylation of multiple substrates. Inhibitor studies revealed that these responses were required for degranulation and TNF-a synthesis. Both FcgammaRI and FcepsilonRI aggregation also activated the MAP kinases ERK 1/2, JNK and p38 and this was necessary for TNF-alpha synthesis, but not degranulation for both receptors. Thus, signaling events in HuMC following aggregation of FcgammaRI were generally similar to those observed following FcepsilonRI aggregation. The one exception was that, although phosphatidylinositol-3-kinase was activated after both FcepsilonRI and FcgammaRI aggregation, only the FcgammaRI appeared to require this molecule for degranulation.