细胞核中IL-33的功能及在炎症疾病中的作用研究

Chronic inflammatory diseases, including allergy and asthma are common disorders with unmet clinical needs. Improved understanding of the regulation and dysregulation of inflammation will improve therapeutic options. Interleukine-33 (IL-33) is an important member of the IL-1 cytokine family which can exist in two forms; as an intracellular nuclear factor or when released as a cytokine. Therefore it has potential dual-functionality; acting as a cytokine which can signal via its receptor ST2 on target cells, and also as a nuclear factor inside the cell. While the role of the cytokine form of IL-33, as an immune alarmin, in inflammatory disease has been well studied, the importance of nuclear IL-33 in immunity and disease, in particularly allergic disorders and the potential interaction between nuclear and cytokine IL-33 in vivo is unknown due to the lack of a suitable experimental system. Our pilot data show that nuclear form IL-33 (nIL-33) is largely induced by the cytokine form of IL-33 via ST2 in inflammatory condition in an autocrine and/or paracrine manner and that nIL-33 can suppress inflammatory gene expression and function, including IL-33. These results suggest that inflammation-enhanced nIL-33 may have a key homeostatic role in inflammatory disease which feedback protects host from inflammatory response-mediated tissue damage and mortality. Given many inflammatory, allergic and infectious conditions can lead to the release of cytokine IL-33, we therefore propose a novel regulatory feedback loop of cytokine IL-33-ST2-nIL-33 pathway in the modulation of cytokine IL-33 and other inflammatory/pathogenic mediators-mediated inflammatory gene expression and activation in infectious and inflammatory conditions. The overall goal of this work is to define the regulatory effect of nIL-33 in allergic asthma in vivo and to identify the molecular targets through which nIL-33 exerts its regulatory activity on inflammatory gene, including IL-33 gene, expression and function in vitro and in vivo. This research will not only define the mechanisms by which nIL-33 controls inflammation thereby identifying robust novel molecular target against which novel therapeutic strategies can be developed..To achieve this goal the following specific objectives will be met:.1).Define the role of nIL-33 in the regulation of transcription and map nIL-33 chromatin interactions..2).Establish novel murine experimental systems in order to define the regulatory effect of nIL-33 on inflammatory diseases in vivo. .3).Determine the impact of nIL-33 on the pathology of mouse models of asthma.

IL-33是IL-1家族的重要成员，具有细胞核内外双重免疫调节功能。细胞因子IL-33通过受体ST2在多种疾病，包括炎症、特别是过敏性哮喘病中发挥重要作用。细胞内IL-33主要定位于细胞核，IL-33 N末端(Nt)可能通过与组蛋白或NF-κB相互作用来调控基因的表达。近期我们的体外研究表明核IL-33具有转录调控功能，不仅能调控LPS也能调节细胞因子IL-33的功能。然而，由于缺乏有效的体内研究系统，核IL-33（nIL-33）在疾病中的作用和重要性尚且未知。本项目拟利用il33-/-和ST2-/-小鼠构建全长(FL)和N 端IL-33转基因细胞系和小鼠模型，揭示nIL-33的核功能及其与转录调控的关系，阐明nIL-33在调节炎症及过敏性哮喘中的重要性，为炎症疾病的治疗提供一个新途径。

IL-33是IL-1家族的重要成员，具有细胞核内外双重功能，其释放到胞外后通过受体ST2引发类似过敏性哮喘病的发生。此外，细胞因子IL-33/ST2通路在多种炎症、自身免疫性疾病、肿瘤等病理过程中发挥重要作用，提示该通路可作为多种疾病治疗的潜在靶点。细胞内IL-33主要定位于细胞核，而核IL-33（nIL-33）的生物学作用及在疾病中的作用和重要性未知。近期我们发现NtIL-33具有转录调控功能。体外研究表明nIL-33不仅能调控LPS也能调节细胞因子IL-33的功能。本项目通过构建NtIL-33 knock in小鼠、il33-/-、flIL-33tg、ST2-/-小鼠模型，揭示nIL-33的核功能及其与转录调控的关系，证实了IL-33对NF-κB靶基因的转录抑制功能不依赖其细胞表面受体ST2而依赖于其细胞核功能。通过构建内毒素休克及过敏性哮喘模型并对表型进行分析，明确了细胞核中IL-33的重要免疫炎症抑制功能。本项目阐明了nIL-33在调节炎症及过敏性哮喘疾病中的重要性，为炎症疾病的治疗提供一个新途径。

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