Modulation of IL-5 Mediated Inflammation

描述（由申请人提供）：白细胞介素-5（IL-5）是一种造血细胞因子，其特异性促进嗜酸性粒细胞的分化、存活和功能，并且被认为是过敏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-5 R）是由IL-5特异性α链（IL-5 R α）和共同β链（β c）组成的异二聚体，其单独不结合IL-5，但对于激动性信号转导是必需的，并且与IL-3R α和GM-CSFRa共享用于信号传导。 该提案的总体目标是了解通过IL-5 R的ac亚基调节IL-5信号传导的机制。我们以前的研究描绘了IL-5的功能结构和IL-5内与IL-5 R α和β受体亚基结合的结合结构域。我们对这种竞争性更新的初步研究表明，IL-5信号通过交流可能依赖于周围的glu 13 IL-5残基的构象电荷场。 此外，我们还发现IL-5 R的IL-5激动性连接还启动IL-5信号传导的蛋白酶体终止，这导致细胞对ac接合细胞因子IL-3、IL-5和GM-CSF中的每一种的同型和异型脱敏。 本项目的具体目标是：1）确定ac功能性连接所需的IL-5残基; 2）确定调节蛋白酶体终止ac信号传导的分子机制; 3）研究蛋白酶体介导的ac异型脱敏调节IL-5应答细胞终末分化和功能的可能性;和4）探索共享细胞因子受体亚基的蛋白酶体降解作为细胞因子信号传导的同型和异型脱敏的保守生理机制的潜力。

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.