The role of novel IL-1 like cytokines in asthma

描述（由申请人提供）：哮喘影响全球3亿人。由于哮喘是一种异质性疾病，由炎症刺激产生的多种细胞因子协同作用驱动，表征个体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对于制定更好的治疗干预策略是必要的。该项目的目的是产生缺乏细胞因子IL-1F6 （IL-36¿），IL-1F9 （IL-36?）及其受体IL-1RL2 （IL-36R）的小鼠，并进行概念验证研究，以确定这些细胞因子的个体或集体缺乏是否会减轻小鼠模型中的哮喘。IL-1F6和IL-1F9是与经典IL-1分子（IL-1¿，IL-1¿）具有结构和功能相似性的新型细胞因子，但与经典IL-1受体IL-1RL2结合而不是与经典IL-1受体IL-1R1结合。我们和其他人报道了IL-1F6和IL-1F9主要在气道上皮细胞中表达。最近的报道表明，这些细胞因子的受体IL-1RL2在骨髓来源的树突状细胞和CD4+淋巴细胞中表达，这些细胞类型在哮喘发病中起关键作用。我们之前的研究表明，IL-1F9在过敏原挑战小鼠的肺部上调，气管内给药重组IL-1F9诱导促炎趋化因子核因子κ B (NF-？B)小鼠肺部的活化和中性粒细胞内流。此外，IL- 1f6和IL- 1RL2在皮肤炎症和牛皮癣的发展中发挥促炎作用。虽然这些积累的证据强调了这些新型细胞因子在炎症性疾病中的重要性，但内源性产生的IL-1F6、IL-1F9和IL-1RL2在炎症背景下的确切作用仍然是未知的，因为缺乏商业上可用的IL-1F6、IL-1F9和IL-1RL2缺陷小鼠。因此，本研究将产生新的试剂来阐明IL-1F6、IL-1F9和IL-1RL2在小鼠哮喘模型中的功能影响。这些研究将为未来研究这些新型细胞因子介导的调节机制铺平道路，这些细胞因子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。

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.