Generation of IL-33 Deficient Mice

描述（由申请人提供）：该项目的目的是产生IL-33缺陷小鼠并对其进行初步表征。IL-33是最近发现的白介素-1家族成员，该家族包括IL-1- α， IL-1- β和IL-18。2005年11月，IL-33被确定为白细胞介素-1受体家族成员ST2（正式名称IL1RL1）的细胞外配体。IL-33作为ST2受体的细胞外配体，在过敏和免疫疾病中具有强大的免疫调节功能，这方面的研究文献迅速增加。IL-33与2003年发现的一种名为高内皮小静脉核因子（NF-HEV）的分子相同，后者是一种在内皮中高度表达的核因子，具有转录抑制因子的特性。内源性核IL-33在内皮细胞和上皮细胞中表达，代表IL-33在慢性炎症中的调节的一种附加模式。在IL-33被鉴定为ST2受体的配体之前，ST2受体在临床和实验研究中已经与炎症性哮喘、肺纤维化、血管疾病、败血症和心脏病相关。虽然目前有ST2受体敲除小鼠，但它不能解决IL-33在骨髓祖细胞的分泌和扩增、IL-33/ST2L信号的调节以及IL-33在慢性炎症调节中的核功能。基于ST2受体敲除小鼠的生存能力，我们预计IL-33敲除小鼠将是可行的。目前还没有IL-33敲除小鼠，但它很有可能在人类慢性炎症疾病中发现新的调节机制。

DESCRIPTION (provided by applicant): The objective of this project is to generate IL-33 deficient mice and to subject them to initial characterization. IL-33 is a recently identified member of the interleukin-1 family, which includes IL-1- alpha, IL-1-beta and IL-18. In November 2005, IL-33 was identified as the extracellular ligand for an interleukin-1 receptor family member, ST2 (official name IL1RL1). The rapidly expanding literature on IL- 33 shows that as an extracellular ligand for the ST2 receptor, IL-33 has potent immunomodulary functions in allergy and immune diseases. IL-33 is identical to a molecule discovered in 2003 called Nuclear Factor of High Endothelial Venules (NF-HEV), a nuclear factor highly expressed in the endothelium with transcriptional repressor properties. Endogenous nuclear IL-33 is expressed in endothelial and epithelial cells representing an addition mode of IL-33 regulation in chronic inflammation. Prior to the identification of IL-33 as the ligand for the ST2 receptor, the ST2 receptor had been associated with inflammatory asthma, pulmonary fibrosis, vascular diseases, sepsis and heart disease in clinical and experimental studies. While an ST2 receptor knockout mouse is currently available, it cannot address the roles of IL-33 in bone marrow progenitor cell egress and expansion, regulation of IL-33/ST2L signaling, and nuclear functions of IL-33 in the regulation of chronic inflammation. Based on the viability of ST2 receptor knockout mice, we anticipate that IL-33 knockout mice will be viable. An IL-33 knockout mouse, which is currently not available, has a high potential to identify novel regulatory mechanisms in human chronic inflammatory diseases. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE The objective of this project is to generate IL-33 deficient mice. IL-33 is a member of the interleukin-1 family that was recently identified as the extracellular ligand for an interleukin-1 receptor family member, ST2. The rapidly expanding literature on IL-33 shows that as an extracellular ligand for the ST2 receptor, IL-33 has potent immunomodulary functions in allergy and immune diseases. An IL-33 knockout mouse, which is currently not available, has a high potential to identify novel regulatory mechanisms in human pulmonary and chronic inflammatory diseases.