Analysis of molecular mechanisms on cytoprotective effect of thioredoxin for host defense and aging prevention

硫氧还蛋白对宿主防御和衰老预防的细胞保护作用的分子机制分析

• 批准号: 12670113
• 负责人: NAKAMURA Hajime
• 金额: $ 2.05万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670113/
• 关键词: THIOREDOXIN; STRESS; TRANSGENIC MICE; LEUKOCYTE; INTERSTITIAL PNEUMONIA; REDOX; HOST DEFENSE; AGING

Roles of thioredoxin (TRX) in host defense was investigated using TRX transgenic (TRX Tg) mice. TRX Tg mice were resistant to a variety of oxidative stresses. Compared with wild type C57BL/6 mice, TRX Tg mice were more resistant to cerebral and renal ischemia and showed roughly 25% longer survival period. TRX Tg mice were more resistant to bleomycin- and cytokine-induced insterstitial pneumonia and influenza virus-induced pneumonia. To address the underlying mechanisms, effects of TRX was investigated in the mouse air pouch chemotaxis model. Lipopolysaccharide (LPS)-induced neutrophil extravasation was significantly inhibited by intravenously injected recombinant TRX or in TRX Tg mice. TRX suppressed p38 MAPK activation, downregulation of CD62L (L-Selectin) and adhesion on endothelial cells of LPS-stimulated neutrophils. These results provide a possible new explanation on the cytoprotective and anti-inflammatory effect of TRX in addition to its antioxidant effect. Clinical application of TRX for host defense and aging prevention is now under investigation.

利用硫氧还蛋白（TRX）转基因小鼠（TRX Tg）研究了TRX在宿主防御中的作用。TRX Tg小鼠对各种氧化应激具有抗性。与野生型C57 BL/6小鼠相比，TRX Tg小鼠对脑和肾缺血的抵抗力更强，存活期延长约25%。TRX Tg小鼠对博来霉素和马诺啡肽诱导的间质性肺炎和流感病毒诱导的肺炎更具抗性。为了解决潜在的机制，在小鼠气囊趋化模型中研究了TRX的作用。脂多糖（LPS）诱导的中性粒细胞外渗显着抑制静脉注射重组TRX或TRX Tg小鼠。TRX抑制p38 MAPK活化，下调CD 62 L（L-选择素）和LPS刺激的中性粒细胞对内皮细胞的粘附。这些结果为TRX除抗氧化作用外的细胞保护和抗炎作用提供了可能的新解释。TRX在宿主防御和衰老预防方面的临床应用正在研究中。

项目成果

K.Shioji, et al.(7名、3番): "Upregulation of thioredoxin expression in giant cell myocarditis in rats"FEBS Letter. 472. 109-113 (2000)

K.Shioji 等人（7 人，第 3 期）：“大鼠巨细胞心肌炎中硫氧还蛋白表达的上调”FEBS Letter。472. 109-113 (2000)

H. Nakamura, et al.: "Enhanced resistancy of thioredoxin-transgenic mice against influenza virus-induced pneumonia"Immunology Letters. (in press).

H. Nakamura等人：“硫氧还蛋白转基因小鼠对流感病毒诱导的肺炎的抵抗力增强”免疫学快报。

H.Nakamura, et al.(10名、1番): "Expression of Thioredoxin and Glutaredoxin, Redox-Regulating Proteins, in Pancreatic Cancer"Cancer Detection and Prevention. 24. 53-60 (2000)

H. Nakamura 等人（10 人，第 1 期）：“胰腺癌中氧化还原调节蛋白的表达”，24. 53-60 (2000)。

H.Nakamura, et al.: "Circulating thioredoxin suppresses lipopolysaccharide-induced neutrophil chemotaxis"Proceedings of National Academy of Science USA. 98. 15143-15148 (2001)

H.Nakamura 等人：“循环硫氧还蛋白抑制脂多糖诱导的中性粒细胞趋化性”美国国家科学院院刊。

H.Nakamura, et al.: "Thioredoxin overexpression in transgenic mice"Methods in Enzymology. 347. 436-440 (2002)

H.Nakamura 等人：“转基因小鼠中硫氧还蛋白过度表达”酶学方法。