Control of IgG-mediated Inflammation by Fyn and Lyn Kinases

Fyn 和 Lyn 激酶控制 IgG 介导的炎症

• 批准号: 8500877
• 负责人: John J Ryan
• 金额: $ 35.08万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-15 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500877
• 关键词: Anaphylaxis; Arthritis; Basophils; Biological Assay; Cytokine Network Pathway; Disease; Etiology; Fc Receptor; Feedback; Genetic Polymorphism; Genotype; Homeostasis; Human; IgG Receptors; Immunoglobulin G; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-4; Mediating; MicroRNAs; Modeling; Mus; Myelogenous; Myeloid Cells; Pathway interactions; Phenotype; Phosphotransferases; Production; Receptor Signaling; Resistance; Rheumatoid Arthritis; Role; Signal Transduction; Testing; autoimmune arthritis; cytokine; in vivo; macrophage; mast cell; neutrophil; new therapeutic target; public health relevance; receptor; receptor expression; research study; response; transcription factor

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. !

描述（由申请人提供）：Fc?？在炎症反应中，IgG的受体参与对激活髓细胞至关重要。我们发现IgG信号需要Fyn激酶，并被Lyn抑制。这在Fc？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Stat5，其缺失大大减少了细胞因子的产生。Fc ?R反应受到细胞因子的修饰。例如，IL-4增强炎症IgG受体的表达和细胞因子的分泌。相比之下，TGF？1能拮抗细胞因子的产生，选择性地降低Fyn和Stat5的表达。TGF吗?1效应在th2易感小鼠的肥大细胞中不存在，这与缺乏tgf诱导的能够靶向Fyn和Stat5的microrna有关。我们假设IL-4和TGF？1通过控制Fyn/Lyn-Stat5通路部分调节igg介导的炎症。失调的igg介导的信号，可能是由于对细胞因子的遗传易感反应，可能是炎症性关节炎的病因。！ 我们将通过体外机制实验和体内功能分析来验证这一假设。我们的具体目标是：1 .验证Fyn和Lyn对Fc？R信号，包括Stat5通路。2。来验证Fc？r介导的炎症由包括IL-4和TGF - 1在内的细胞因子网络控制。！