IL-10 Controls Mast Cell Homeostasis

IL-10 控制肥大细胞稳态

• 批准号: 9204527
• 负责人: John J Ryan
• 金额: $ 2.17万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204527
• 关键词: 129/Sv Mouse; Acute; Affinity; Allergic Disease; Anaphylaxis; Asthma; Basophils; Cell physiology; Cells; Chronic; Disease; Environment; Etiology; Feedback; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genotype; Health; Homeostasis; Human; IgE; IgE Receptors; Immune; In Vitro; Inbred BALB C Mice; Inflammation; Inflammatory; Inflammatory Response; Interleukin-10; Mediating; MicroRNAs; Mus; Pathway interactions; Phenotype; Phosphorylation; Process; Production; Regulation; Resistance; Role; Sentinel; Serine; Signal Transduction; Testing; Th1 Cells; Th2 Cells; Tyrosine Phosphorylation; airway hyperresponsiveness; autocrine; cytokine; in vivo; in vivo Model; mast cell; response

DESCRIPTION (provided by applicant): Mast cells reside at the host-environment interface, serving as immune sentinels in both protective and pathological responses. The high affinity IgE receptor, Fc?RI, is the best-understood mast cell-activating pathway. Mast cell homeostasis is likely regulated by cytokines produced in the inflammatory response, perhaps in an autocrine fashion. We demonstrate that IL-10 suppresses Fc?RI-mediated activation by targeting Fyn, Stat5, and Akt for degradation. Importantly, this suppression is observed in mast cells from Th1-prone C57BL/6 but not Th2-prone BALB/c or 129/Sv mice. IL-10 sensitivity correlates with the induction of microRNAs (miRs) potentially targeting Fyn, Stat5B, and Akt. While Fyn is known to activate Akt, the role of Stat5 is less understood. We find that Stat5B is critical for Fc?RI-induced cytokine production. We demonstrate that Stat5 tyrosine phosphorylation is Fyn-dependent and that Fyn physically interacts with Stat5. Stat5 is also serine phosphorylated during IgE signaling, through a Fyn-independent pathway. We will determine how the Fyn-Stat5/Akt pathway is regulated by IL-10, and if resistance to this suppression correlates with allergic disease. Our hypothesis is that Fc?RI activation is limited by feedback signaling via IL-10-induced miRs that selectively dampen the Fyn-Stat5/Akt pathway. Loss of this regulation in a non-permissive genetic background could be part of atopic etiology. Specific Aims I. To test the hypothesis that IL-10 antagonizes the Fyn-Stat5/Akt pathway via genotype-restricted effects on miR induction in mast cells and basophils. II. To test the hypothesis that Stat5B is critical for Fc?RI signaling in mast cells and basophils. III. To test the hypothesis that IL-10 suppresses Fc?RI responses in vivo by antagonizing the Fyn-Stat5/Akt pathway.

描述（由申请人提供）：肥大细胞位于宿主-环境界面，在保护性和病理性反应中充当免疫哨兵。高亲和力IgE受体，Fc？RI是最好理解的肥大细胞活化途径。肥大细胞的稳态可能是由炎症反应中产生的细胞因子调节的，可能是以自分泌的方式。我们表明，IL-10抑制Fc？通过靶向Fyn、Stat 5和Akt降解的RI介导的活化。重要的是，这种抑制作用在Th 1-倾向C57 BL/6的肥大细胞中观察到，但在Th 2-倾向BALB/c或129/Sv小鼠中没有观察到。IL-10敏感性与潜在靶向Fyn、Stat 5 B和Akt的microRNA（miR）的诱导相关。虽然已知Fyn可以激活Akt，但Stat 5的作用还不太清楚。我们发现，Stat 5 B是关键的Fc？RI诱导的细胞因子产生。我们证明，Stat 5酪氨酸磷酸化是Fyn依赖的，Fyn物理相互作用与Stat 5。Stat 5在IgE信号传导过程中也通过Fyn非依赖性途径被丝氨酸磷酸化。我们将确定Fyn-Stat 5/Akt通路如何受IL-10调节，以及对这种抑制的抵抗是否与过敏性疾病相关。我们的假设是，Fc？RI激活受到经由IL-10诱导的miR的反馈信号传导的限制，所述miR选择性地抑制Fyn-Stat 5/Akt途径。在非允许的遗传背景下这种调节的丧失可能是特应性病因的一部分。 具体目标一。为了检验IL-10通过基因型限制对肥大细胞和嗜碱性粒细胞中miR诱导的作用拮抗Fyn-Stat 5/Akt通路的假设。二.为了检验Stat 5 B对Fc至关重要的假设？肥大细胞和嗜碱性粒细胞中的RI信号传导。三.为了检验IL-10抑制Fc？通过拮抗Fyn-Stat 5/Akt途径在体内应答RI。