IL-10 Controls Mast Cell Homeostasis

描述（由申请人提供）：肥大细胞驻留在宿主-环境界面，在保护性和病理反应中充当免疫哨兵。高亲和力IgE受体Fc？RI是我们最了解的肥大细胞激活途径。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。我们证明IL-10抑制Fc？通过靶向Fyn、Stat5和Akt介导的ri介导的降解激活。重要的是，这种抑制在th1易感性的C57BL/6小鼠的肥大细胞中观察到，而在th2易感性的BALB/c或129/Sv小鼠中没有观察到。IL-10敏感性与诱导潜在靶向Fyn、Stat5B和Akt的microrna （miRs）相关。虽然已知Fyn可以激活Akt，但Stat5的作用尚不清楚。我们发现Stat5B对Fc？ri诱导的细胞因子产生。我们证明Stat5酪氨酸磷酸化是Fyn依赖的，并且Fyn与Stat5物理相互作用。Stat5在IgE信号传导过程中也通过fyn不依赖的途径被丝氨酸磷酸化。我们将确定IL-10如何调节Fyn-Stat5/Akt通路，以及对这种抑制的抗性是否与过敏性疾病相关。假设是Fc？通过il -10诱导的miRs选择性抑制Fyn-Stat5/Akt通路的反馈信号限制了RI的激活。在不允许的遗传背景下失去这种调节可能是特应性病因的一部分。1 .验证IL-10通过抑制肥大细胞和嗜碱性细胞miR诱导而拮抗Fyn-Stat5/Akt通路的假设。2。为了验证Stat5B对Fc？肥大细胞和嗜碱性细胞中的RI信号。3。为了验证IL-10抑制Fc？通过拮抗Fyn-Stat5/Akt通路在体内的RI反应。

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.