Control of IgG-mediated Inflammation by Fyn and Lyn Kinases

描述（由申请人提供）：Fc？？IgG的受体结合对于在炎症反应期间激活骨髓细胞是关键的。我们发现，IgG信号需要Fyn激酶，并被林恩抑制。这在Fc的模型中是一致的吗？受体（Fc？R）诱导的过敏性休克，其中林恩缺失加剧了反应。我们注意到，Fc？R激活Stat 5，其缺失大大减少了细胞因子的产生。FC？R反应被细胞因子修饰。例如，IL-4增强炎性IgG受体表达和细胞因子分泌。相比之下，TGF？1拮抗细胞因子的产生并选择性地降低Fyn和Stat 5的表达。转化生长因子1效应在来自Th 2易感小鼠的肥大细胞中不存在，这与缺乏能够靶向Fyn和Stat 5的TGF诱导的microRNA相关。我们推测，IL-4和TGF？1部分通过控制Fyn/Lyn-Stat 5途径调节IgG介导的炎症。IgG介导的信号转导失调，可能是由于对细胞因子的遗传易感性反应，可能是炎性关节炎的病因学起源。!我们将通过体外机制实验和体内功能测定来验证这一假设。我们的具体目标是：一。要测试的假设，Fyn和林恩提供拮抗控制Fc？R信号传导，包括Stat 5途径。二.为了检验这个假设，Fc？R-介导的炎症是由细胞因子网络，包括IL-4和TGF？1. !

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. !