Investigation of human mast cell biological function induced by FcγRI aggregation

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We have previously reported that human mast cells express a functional high affinity IgG receptor, FeγRI and its expression is up-regulated by IFN-γ(J Immunol,2000,164:4332). Following FcγRI aggregation, human mast cells release and synthesize histamine and lipd mediators, and also produce a various cytokines, especially proinflammatory cytokines such as TNF-α and IL-1β(J Immunol,2001,166:4705,Eur J Immunol,2001,31:3298). We examined FcγRI -dependent activation of specific signal transduction molecules and determined the relative involvement of these events in human mast cell degranulation and TNF-α production following both FcγRI and FcεRI aggregation. Signaling events in human mast cells 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 (Okayama Y, et al. Eur J Immunol,2003,33,1450. Furthermore, we demonstrated that the release of preformed mast cell-associated TNF-a acts as a positive autocrine feedback signal to augment NF-kB activation and production of further cytokine, including GM-CSF and IL-8 (J Immunol,2002,169:5287). To systematically explore how human mast cells modulate immune system following FcεRI and FcγRI aggregation, we used high-density oligonucleotide probe arrays to compare the IgE/anti-IgE-induced gene expression profile with IgG1/ant-IgG1-mediated profile in mast cells. Both expression profiles were similar, but specific gene expression profile mediated by FcγRI aggregation was identified (Okayama Y, et al. in preparation). We also found that a functional Toll-like receptor 4 (TLR4) was up-regulated by IFN-γ(Okumura S, et al. Blood,2003,102:2547). These findings suggest that FcγRI expressed on human mast cells, appears to have different physiological and pathlogical function in Th1 environment from FcεRI.