Role of CD14 in bacterial infection, and search and regulation of molecules in early signal transduction

CD14在细菌感染中的作用及早期信号转导分子的寻找和调控

• 批准号: 11671171
• 负责人: HIJIYA Naoki
• 金额: $ 2.3万
• 依托单位: OITA MEDICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671171/
• 关键词: CD14; knock out; TLR-4; E.coli; transgenic; LPS; Shwartzman reaction; ノックアウト; トランスジェニック; TLR4; TLR2; HUVEC

Despite the lack of a proinflammatory response to LPS, CD14-deficient mice clear E.coli at least 10 times more efficiently than normal mice. In this study, we show that this is due to an early and intense recruitment of PMN following the injection of Gram-negative bacteria or LPS in CD14-deficient mice ; in contrast, PMN infiltration is delayed by 24 h in normal mice. Similar results of early LPS-induced PMN infiltration and enhanced clearance of E.coli were seen in Toll-like receptor (TLR) 4-deficient mice. Furthermore, the lipid A moiety of LPS induced early PMN infiltration not only in CD14-deficient and TLR-4-deficient mice, but also in normal mice. In conclusion, the lipid A component of LPS stimulates a unique and critical pathway of innate immune responses that is independent of CD14 and TLR4 and results in early PMN infiltration and enhanced bacterial clearance.Transgenic mice which secreted the amino terminal 71 amino acids of mouse CD14 under the control of al-antitrypsin promoter were produced. The mice were shown to be significantly resistant to systemic lethal Shwartzman reaction.A candidate protein which were implicated in the early cell surface signaling of LPS was selected by pharge display analysis.

尽管缺乏对LPS的促炎反应，但CD 14缺陷小鼠清除大肠杆菌的效率比正常小鼠高至少10倍。在这项研究中，我们表明，这是由于早期和激烈的招聘后，注射革兰氏阴性菌或LPS在CD 14缺陷小鼠的PMN;相反，PMN浸润延迟24小时，在正常小鼠。在Toll样受体（TLR）4缺陷小鼠中观察到早期LPS诱导的PMN浸润和大肠杆菌清除增强的类似结果。此外，LPS的脂质A部分不仅在CD 14缺陷和TLR-4缺陷小鼠中诱导早期PMN浸润，而且在正常小鼠中也诱导早期PMN浸润。总之，LPS的脂质A组分刺激了一个独特的和关键的先天性免疫反应途径，该途径不依赖于CD 14和TLR 4，导致早期PMN浸润和增强细菌清除。通过噬菌体展示分析筛选出一个与LPS早期细胞表面信号转导有关的候选蛋白。

项目成果

Eubanks,J.W.: "Acute pancreatitis induces cytokine production in endotoxin-resistant"Ann.Surg.. 227(6). 904-911 (1998)

Eubanks，J.W.：“急性胰腺炎诱导内毒素抗性细胞因子的产生”Ann.Surg. 227(6)。

Haziot,A,: "Role of CD14 in infection:studies in CD14-deficient mice,"Prog.Clin.Biol.Res.. 397. 255-260 (1998)

Haziot,A,：“CD14 在感染中的作用：CD14 缺陷小鼠的研究”，Prog.Clin.Biol.Res.. 397. 255-260 (1998)

Haziot,A,: "Role of CD14 in infection:studies in CD14-deficient mice."Wiley-Liss. 6 (1998)

Haziot,A,：“CD14 在感染中的作用：CD14 缺陷小鼠的研究。”Wiley-Liss。

Yasui,A.: "Leukocyte Typing VII White Cell Differentiation"Oxford University Press(in press).

Yasui,A.：“白细胞分型 VII 白细胞分化”牛津大学出版社（正在出版）。

Hijiya N, Higuchi, Y., Matsuura, K.: "The function of CD14 in infection"Molecular Medicine. 36(5). 476-486 (1999)

Hijiya N、Higuchi, Y.、Matsuura, K.：“CD14 在感染中的功能”分子医学。