The role of novel IL-1 like cytokines in asthma

描述(申请人提供)：全球有3亿人患有哮喘。由于哮喘是一种由炎症刺激产生的多种细胞因子协同作用所驱动的异质性疾病，因此有必要确定单个细胞因子在哮喘发病机制中的比例贡献、功能重要性和相关性，以制定更好的治疗干预策略。本项目的目的是培育细胞因子IL-1F6、IL-1F9缺陷的小鼠。以及它们的受体IL-1RL2(IL-36R)，并进行概念验证研究，以确定这些细胞因子的单独或集体缺乏是否可以减轻小鼠模型中的哮喘。IL-1F6和IL-1F9是一种新的细胞因子，它们在结构和功能上与经典的IL-1分子(IL-1、IL-1)相似，但它们结合的是一种新的受体IL-1RL2，而不是经典的IL-1受体IL-1R1。我们和其他人已经报道，IL-1F6和IL-1F9主要在呼吸道上皮细胞中表达。最近的报道表明，这些细胞因子的受体IL-1RL2表达于骨髓来源的树突状细胞和CD4+淋巴细胞，这两种细胞在哮喘发病机制中起着关键作用。我们先前已经证明，IL-1F9在过敏原攻击小鼠的肺组织中上调，并经气管内注射重组IL-1F9诱导小鼠肺内产生促炎性趋化因子、核因子-kappaB(NF-？B)激活和中性粒细胞内流。此外，IL-1F6和IL-1RL2在皮肤炎症和银屑病的发生发展中发挥促炎作用。虽然越来越多的证据强调了这些新的细胞因子在炎症性疾病中的重要性，但由于缺乏商业上可用的IL-1F6、IL-1F9和IL-1RL2缺陷小鼠，内源性产生的IL-1F6、IL-1F9和IL-1RL2在炎症背景下的确切作用仍不清楚。因此，建议的研究将产生新的试剂来阐明IL-1F6、IL-1F9和IL-1RL2在哮喘小鼠模型中的功能影响。这些研究将为未来研究这些新的细胞因子介导的调控机制铺平道路，这些调控机制可能对人类哮喘和其他炎症性肺部疾病具有潜在的治疗意义。 公共卫生相关性：由于哮喘作为一种疾病的复杂性，新的治疗方法仍然难以捉摸。识别和表征调控哮喘发病机制的新的内源性介质对于更好地了解哮喘发病和持续期间潜在的治疗干预点是至关重要的。本应用旨在进行试剂生成和初步研究，以表征新的白细胞介素1(IL-1)样细胞因子及其受体(IL-1F6、IL-1F9和IL-1RL2)在哮喘发病机制中的作用。这项研究的结果将为这些细胞因子在哮喘中的功能相关性和治疗潜力提供关键的见解。

DESCRIPTION (provided by applicant): Asthma affects 300 million people worldwide. Since asthma is a heterogeneous disorder driven by concerted effects of multiple cytokines produced in response to inflammatory stimuli, characterization of the proportional contribution, functional importance and relevance of individual cytokines in asthma pathogenesis is necessary to develop better strategies for therapeutic intervention. The objective of this project is to generat mice deficient in the cytokines IL-1F6 (IL-36¿), IL-1F9 (IL-36?) and their receptor IL-1RL2 (IL-36R), and perform proof-of-concept studies to determine if individual or collective deficiency of these cytokines attenuates asthma in murine models. IL-1F6 and IL-1F9 are novel cytokines that possess structural and functional similarity to classical IL-1 molecules (IL-1¿, IL-1¿), but bind to a novel receptor IL-1RL2 instead of the classical IL-1 receptor IL-1R1. We and others have reported that IL-1F6 and IL-1F9 are expressed predominantly in airway epithelial cells. Recent reports have demonstrated that IL-1RL2, the receptor for these cytokines, is expressed in bone marrow derived dendritic cells and CD4+ lymphocytes, cell types that play a critical role in asthma pathogenesis. We have previously shown that IL-1F9 is upregulated in the lungs of allergen challenged mice and intratracheal administration of recombinant IL-1F9 induced proinflammatory chemokine production, Nuclear factor kappa B (NF-?B) activation and neutrophil influx in the lungs of mice. In addition, IL-1F6 and IL- 1RL2 exert proinflammatory effects in the development of skin inflammation and psoriasis. While such accumulating evidence emphasizes the importance of these novel cytokines in inflammatory diseases, the exact role of endogenously produced IL-1F6, IL-1F9 and IL-1RL2 in the context of inflammation is still uncharacterized due to the lack of commercially available IL-1F6, IL-1F9 and IL-1RL2 deficient mice. Therefore, the proposed studies will generate novel reagents to clarify the functional impact of IL-1F6, IL-1F9 and IL-1RL2 in murine models of asthma. These studies will pave way for future investigation of regulatory mechanisms mediated by these novel cytokines that may be of potential therapeutic importance in human asthma and other inflammatory lung diseases. PUBLIC HEALTH RELEVANCE: Due to the complexity of asthma as a disease, novel therapies remain elusive. Identification and characterization of novel endogenous mediators that regulate asthma pathogenesis is essential to gain a better understanding of potential therapeutic intervention points during the onset and persistence of asthma. This application seeks to perform reagent generation and pilot studies to characterize the role of novel Interleukin-1 (IL-1) like cytokines and their receptors (IL-1F6, IL-1F9 and IL-1RL2) in asthma pathogenesis. Results from this study will provide critical insights into the functional relevance and therapeutic potential of these cytokines in asthma.