Fc Receptors in Mast Cell Signaling and Function

肥大细胞在哮喘和其他过敏性疾病的发病机制中起着关键作用。这些反应通常由细胞表面上表达的高亲和力IgE受体（Fc-IgE-RI）的抗原依赖性聚集和随后促炎介质（例如组胺、前列腺素类、蛋白酶和细胞因子）的释放引发。我们已经证明，干扰素-γ上调培养的人肥大细胞上的IgG（Fc-γ-RI）的高亲和力受体，并且这些受体的聚集导致肥大细胞介质释放。本研究的目的之一是阐明Fc-γ-RI和Fc-γ-RI受体导致人肥大细胞释放炎症介质的信号通路。目前将Fc-γ-RI与肥大细胞活化联系起来的信号通路模型主要基于在RBL 2 H3细胞中进行的研究。RBL 2 H3细胞是转化的啮齿类动物细胞系，其在所有方面可能不反映成熟的人肥大细胞。连接Fc-γ-RI受体与肥大细胞活化的信号通路尚未被描述。现在可以在原代培养物中从CD 34阳性多能细胞群中培养人肥大细胞，其数量和纯度足以研究定义的信号传导事件。因此，我们现在正在研究特定的信号通路参与Fc-γ-RI-和Fc-γ-RI-依赖性炎症介质从人肥大细胞释放。

Mast cells play a pivotal role in the pathogenesis of asthma and other allergic diseases. These reactions are generally initiated by antigen-dependent aggregation of the high affinity IgE receptor (Fc-epsilon-RI) expressed on the cell surface and subsequent release of pro-inflammatory mediators (e.g. histamine, prostanoids, proteases and cytokines). We have demonstrated that interferon-gamma up-regulates the high affinity receptor for IgG (Fc-gamma-RI) on cultured human mast cells and that aggregation of these receptors leads to mast cell mediator release. An objectof this study is to delineate the signaling pathways of Fc-epsilon-RI and Fc-gamma-RI receptors leading to the release of inflammatory mediators from human mast cells. The current model for the signaling pathway linking Fc-epsilon-RI to mast cell activation has largely been based on studies conducted in RBL 2H3 cells. RBL 2H3 cells are a transformed rodent cell line, which may not be, in all aspects, reflective of the mature human mast cells. The signaling pathways linking the Fc-gamma-RI receptor to mast cell activation have yet to be delineated. It is now possible to grow human mast cells from a CD34-positive, pluripotent cell population in primary culture with sufficient number and purity to study defined signaling events. Thus, we are now examining specific signaling pathways involved in Fc-epsilon-RI- and Fc-gamma-RI- dependent inflammatory mediator release from human mast cells.