Control of IgG-mediated Inflammation by Fyn and Lyn Kinases

描述(由申请人提供)：在炎症反应过程中，免疫球蛋白Fc？？受体的参与对激活髓系细胞至关重要。我们发现，Ig G信号需要Fyn激酶，并被LYN抑制。这在FC的模型中是一致的吗？受体(Fc？R)诱导的过敏性休克，其中Lyn缺失加剧了反应。我们注意到Fc？R激活了Stat5，它的缺失极大地减少了细胞因子的产生。Fc？R反应受细胞因子的影响。例如，IL-4促进炎性免疫球蛋白受体的表达和细胞因子的分泌。相反，转化生长因子β1拮抗细胞因子的产生，选择性地降低Fyn和Stat5的表达。在Th2倾向的小鼠的肥大细胞中没有转化生长因子-1的作用，这与转化生长因子诱导的能够靶向Fyn和Stat5的microRNAs的缺乏有关。我们推测IL-4和转化生长因子β1部分通过控制Fyn/Lyn-Stat5途径来调节免疫球蛋白介导的炎症反应。免疫球蛋白介导的信号传导失调，可能是由于对细胞因子的遗传易感性反应，可能是炎症性关节炎的病因。好了！我们将通过体外的机械实验和体内的功能测试来验证这一假说。我们的具体目标是：1.验证Fyn和Lyn对Fc？R信号的拮抗控制的假设，包括Stat5途径。2.验证Fc？R介导的炎症是由包括IL-4和TGF？1在内的细胞因子网络控制的假设。

DESCRIPTION (provided by applicant): Fc??receptor engagement by IgG is critical to activating myeloid cells during the inflammatory response. We find that IgG signaling requires Fyn kinase and is suppressed by Lyn. This is consistent in a model of Fc? receptor (Fc?R)-induced anaphylactic shock, where Lyn deletion exacerbates the response. We noted that Fc?R activated Stat5, whose deletion greatly reduced cytokine production. Fc?R responses are modified by cytokines. For example, IL-4 enhances inflammatory IgG receptor expression and cytokine secretion. In contrast, TGF?1 antagonizes cytokine production and selectively decreases Fyn and Stat5 expression. TGF?1 effects are absent in mast cells from Th2-prone mice, correlating with a lack of TGF-induced microRNAs capable of targeting Fyn and Stat5. We hypothesize that IL-4 and TGF?1 regulate IgG-mediated inflammation partly by controlling the Fyn/Lyn-Stat5 pathway. Dysregulated IgG-mediated signaling, perhaps due to genetically predisposed responses to cytokines, may serve as the etiologic origin of inflammatory arthritis. ! We will test this hypothesis with mechanistic experiments in vitro and functional assays in vivo. Our Specific Aims are: I. To test the hypothesis that Fyn and Lyn provide antagonistic control of Fc?R signaling, including the Stat5 pathway. II. To test the hypothesis that Fc?R-mediated inflammation is controlled by a cytokine network that includes IL-4 and TGF?1. !