权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Critical role of IL-18 in endotoxin-induced liver injury.

IL-18 在内毒素诱导的肝损伤中的关键作用。

基本信息

批准号：
09670499
负责人：
TSUTSUI Hiroko
金额：
$ 2.3万
依托单位：
Hyogo College of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670499/
关键词：
interleukin 18 endotoxin liver injury macrophages NK cells caspase-1 receptor for IL-18 knockout mice インターロイキン18 急性肝障害クッパー細胞ナチュラルキラー細胞

项目摘要

IL-18 is a pleiotropic cytokine. IL-18 induces IFN-gamma in lymphocytes, upregulates functional Fas ligand expression of lymphocytes and also augments NK activity. Initially, IL-18 was discovered in the injured liver of the mice that had been sequentially administered with heat-killed Propionibacterium acnes (P.acnes) and endotoxin (LPS). IL- 18 is secreted by LPS-activated P.acnes-elicited Kupffer cells. IL-18 is produced by these cells as biologically inactive precursor form (prolL-18), and prolL-18 is cleaved into mature IL-18 by intracellular cysteine proteinase, caspase-l. In this study, we investigated the precise mechanism how IL-18 is involved in endotoxin-induced liver injury and found the followings. First, IL-18-deficient mice are resistant to endotoxin-induced liver injury, but highly sensitive to endotoxin-induced lethality, suggesting that IL-18 might be critical to endotoxin-induced liver injury. In addition, T cells in IL-18-deficient mice are impaired in the differentiation into Th1, a prototpe to inflammation, and NK activity of the mice also is defective, indicating that IL-18 is essential for functional development of immune system. Second, receptor for IL-18 is constitutively expressed on NK cells, whereas its expression on T cells is induced after stimulation with IL-12. MyD 88, an adapter molecule for the activation of receptor for IL-1 is critical for the signal transduction of IL-18. Lymphocytes from MyD88-deficient mice do not respond to IL-18 as well as IL-1. Third, caspase-1 deficient mice are resistant to the endotoxin-induced liver injury without showing early elevation of serum IL- 18 level, suggesting caspase- 1 is critical for IL- 18 secretion after stimulation with LPS.These results suggested that IL-18 might be an essential factor for endotoxin-induced liver injury.

IL-18是一种多效性细胞因子。IL-18诱导淋巴细胞中的IFN-γ，上调淋巴细胞的功能性Fas配体表达，并且还增强NK活性。最初，IL-18是在小鼠的受损肝脏中发现的，这些小鼠先后接受了热灭活的痤疮丙酸杆菌（P.acnes）和内毒素（LPS）。IL- 18由LPS激活的痤疮丙酸杆菌诱导的库普弗细胞分泌。IL-18由这些细胞作为生物学上无活性的前体形式（proIL-18）产生，并且proIL-18被细胞内半胱氨酸蛋白酶半胱天冬酶-1切割成成熟IL-18。在本研究中，我们研究了IL-18如何参与内毒素诱导的肝损伤的确切机制，并发现以下几点。首先，IL-18缺陷小鼠对内毒素诱导的肝损伤具有抗性，但对内毒素诱导的致死性高度敏感，这表明IL-18可能是内毒素诱导的肝损伤的关键。此外，IL-18缺陷小鼠中的T细胞在分化为Th 1（炎症的原型）方面受损，并且小鼠的NK活性也有缺陷，这表明IL-18对于免疫系统的功能发育是必需的。第二，IL-18的受体在NK细胞上组成型表达，而其在T细胞上的表达在用IL-12刺激后被诱导。MyD 88是IL-1受体活化的衔接分子，在IL-18信号转导中起着关键作用。MyD 88缺陷小鼠的淋巴细胞对IL-18和IL-1没有反应。caspase-1基因缺陷小鼠对内毒素性肝损伤具有抵抗作用，但血清IL- 18水平未出现早期升高，提示caspase- 1在LPS刺激后IL- 18的分泌中起重要作用，提示IL-18可能是内毒素性肝损伤的重要因素。