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Basic Research for Prevention of Interstitial Lung Diseases Induced by IL-18

IL-18所致间质性肺病预防的基础研究

基本信息

批准号：
13670622
负责人：
HOSHINO Tomoaki
金额：
$ 2.3万
依托单位：
KURUME UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670622/
关键词：
Interstitial Lung Diseases Cytokine Chemokine Mouse Model NK Cell 間質性肺炎

项目摘要

IL-18 was discovered as IFN-γ inducing factor (IGIF), and plays important roles in NK cell activation. IL-18 also induces proinflammatory cytokines, chemokines, T helper 2 (Th2) cytokine (e.g. IL-4, IL-13), IgE and IgG1 production. The combination of IL-18 plus IL-2 or IL-12 upregulates IFN-γ gene expression, NK cytotoxicity, and has synergistic anti-tumor activity in vitro and in vitro. Here we report that daily administration of IL-18 with IL-2, but not IL-18 or IL-2 alone induces lethal lung injury in normal mice, but not IL-18Rα (IL-1R related protein) deficient (-/-) mice. Marked interstitial infiltration of lymphocytes, composed mainly of NK cells was found in the lungs of IL-18/IL-2-treated mice. Increased cytokine and chemokine levels were observed in the sera and lungs of IL-18/IL-2-treated mice. Administration of IL-I8/TL-2 was also lethal to mice treated with a metalloproteinase inhibitor, which inhibited TNF-α and FasL release. While IFN-γ (-/-) mice were partially resistant to the treatment, IL-4 (-/-), IL-4/IL-13 (-/-) and Stat6 (-/-) mice were sensitive to the IL-18/IL-2 indicating these genes were not involved in the host response. The lethal effect by IL-I8/IL-2 was completely eliminated in SCID mice pretreated with anti-asialo-GM1 Ab and normal mice pretreated with anti-NK1.1, but not anti-CD4 or anti-CD8 mAb. These results suggest that specific cytokines, chemokines and NK cells are involved in the pathogenesis of interstitial pneumonia. These results suggest that the clinical use of this interleukin may result in unexpected physiological consequences.

IL-18作为IFN-γ诱导因子（IGIF）被发现，在NK细胞活化中起重要作用。IL-18还诱导促炎细胞因子、趋化因子、T辅助细胞2（Th 2）细胞因子（例如IL-4、IL-13）、IgE和IgG 1产生。IL-18加IL-2或IL-12的组合上调IFN-γ基因表达、NK细胞毒性，并且在体外和体外具有协同抗肿瘤活性。我们在此报道了IL-18与IL-2联合给药，而不是IL-18或IL-2单独给药，在正常小鼠中诱导致死性肺损伤，但在IL-18 R α（IL-1 R相关蛋白）缺陷（-/-）小鼠中不诱导致死性肺损伤。在IL-18/IL-2处理的小鼠的肺中发现了主要由NK细胞组成的淋巴细胞的显著间质浸润。在IL-18/IL-2处理的小鼠的血清和肺中观察到增加的细胞因子和趋化因子水平。IL-18/TL-2对金属蛋白酶抑制剂处理的小鼠也具有致死性，其抑制TNF-α和FasL的释放。虽然IFN-γ（-/-）小鼠对治疗部分耐受，但IL-4（-/-）、IL-4/IL-13（-/-）和Stat 6（-/-）小鼠对IL-18/IL-2敏感，表明这些基因不参与宿主应答。在用抗去唾液酸GM 1抗体预处理的SCID小鼠和用抗NK 1.1抗体预处理的正常小鼠中，IL-18/IL-2的致死作用被完全消除，但抗CD 4或抗CD 8 mAb不能。这些结果表明，特异性细胞因子、趋化因子和NK细胞参与了间质性肺炎的发病机制。这些结果表明，这种白细胞介素的临床使用可能会导致意想不到的生理后果。