Modulation of IL-5 Mediated Inflammation

描述(申请人提供)：白介素5(IL-5)是一种造血细胞因子，能促进嗜酸性粒细胞的分化、存活和功能，被认为是变态反应性疾病和哮喘中嗜酸性粒细胞炎症的病理生理学的核心。IL-5受体(IL-5R)是由IL-5特异性α链(IL-5Rα)和公共β链(Betac)组成的异源二聚体，β链单独不与IL-5结合，但对激动型信号转导是必需的，并与IL-3Rα和GM-CSFRα共享信号转导。 这项建议的总体目标是了解通过IL-5R的ac亚单位调节IL-5信号的机制。我们以前的研究描绘了IL-5的功能结构，以及IL-5内与IL-5Rpha和Betac受体亚基结合的结合域。我们对这种竞争性更新的初步研究表明，IL-5通过Ac的信号可能依赖于IL-5的Glu 13残基周围的构象电荷场。此外，我们的新发现是，IL-5激动性连接IL-5R还启动了IL-5信号的蛋白酶体终止，从而导致细胞对AC参与的细胞因子IL-3、IL-5和GM-CSF的同型和异型脱敏。 本项目的具体目标是：1)确定Ac功能连接所需的IL-5残基；2)确定调节Ac终止信号的蛋白酶体的分子机制；3)研究蛋白酶体介导的Ac异型脱敏的可能性，以调节IL-5反应细胞的末端分化和功能；以及4)探索共享的细胞因子受体亚基的蛋白酶体降解作为同型和异型脱敏细胞信号的保守生理机制的可能性。

DESCRIPTION (provided by applicant): Interleukin-5 (IL-5) is a hematopoietic cytokine that specifically promotes the differentiation, survival and function of eosinophils, and is considered central to the pathophysiology of eosinophilic inflammation in allergic disorders and asthma. The IL-5 receptor (IL-5R) is a heterodimer consisting of an IL-5 specific alpha chain (IL-5Ralpha) and a common beta chain (betac) which alone does not bind IL-5, but is necessary for agonistic signal transduction and is shared with the IL-3Ralpha and GM-CSFRalpha for signaling. The overall goal of this proposal is to understand the mechanisms that regulate IL-5 signaling through the ac subunit of the IL-5R. Our previous studies delineated the functional structure of IL-5 and the binding domains within IL-5 that engage the IL-5Ralpha and betac receptor subunits. Our preliminary studies for this competitive renewal suggest that IL-5 signaling through the ac may be dependent on a conformational charge field surrounding the glu 13 residue of IL-5. Furthermore, we made the novel finding that IL-5 agonistic ligation of the IL-5R also initiates proteasome termination of IL-5 signaling that results in both homotypic and heterotypic desensitization of cells to each of the ac engaging cytokines, IL-3, IL-5, and GM-CSF. Specific aims of this project are to: 1) Determine the residues in IL-5 that are required for functional ligation of ac; 2) Determine the molecular mechanisms that regulate proteasome termination of signaling by ac; 3) Investigate the potential for proteasome-mediated heterotypic desensitization of ac to modulate the terminal differentiation and function of IL-5 responsive cells; and 4) Explore the potential for proteasome degradation of shared cytokine receptor subunits to be a conserved physiologic mechanism for both homolypic and heterotypic desensitization of cytokine signaling.