Mechanism of organophosphorus pesticides-induced inhibition of immune function by using perforin knockout mice.

有机磷农药诱导穿孔素基因敲除小鼠免疫功能抑制的机制。

• 批准号: 15590523
• 负责人: LI Qing
• 金额: $ 1.92万
• 依托单位: Nippon Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590523/
• 关键词: NK activity; CTL activity; LAK activity; Perforin; Granzyme; Granulysin; Perforin Knockout mice; Organophosphorus pesticide; perforin; 有機リン農薬; T細胞; マウス; DDVP; granzyme; granulysin; Fasligand; Fas pathway; FACS; NK; CTL; LAK; perforin

NK, LAK and CTL induce cell death in tumor or virus-infected target cells by two main mechanisms. The first mechanism is direct release of cytolytic granules that contain perforin, granzymes, and granulysin by exocytosis to kill target cells. The second mechanism is mediated by the Fas ligand (Fas-L)/Fas pathway.In the present syudy, we examined the effect that dimethyl 2,2-dichlorovinyl phosphate (DDVP), an organophosphorus pesticide has on NK, CTL and LAK activities of PKO mice in vitro using the Fas antigen-positive YAC-1 cell as a target. We found that DDVP significantly decreased NK, CTL and LAK activities in a dose-dependent manner, and that the CTL and LAK activities of PKO mice were significantly blocked by anti-FasL antibody, suggesting that DDVP and anti-FasL antibody have the same/similar mechanism of inhibiting LAK and CTL activities. We further found that DDVP decreases the expression of Fas antigen on YAC-1 cells, and the expression of FasL on LAK cells in a dose-dependent manner, respectively. Taken together, these findings indicate that the DDVP-induced inhibition of NK, LAK and CTL activities in PKO mice is mediated by the impairment of the FasL/Fas pathway. We also found that DDVP not only significantly inhibited activities of granzymes, but also decreased the intracellular level of perforin, granzyme A and granulysin, which was mediated by inducing degranulation of NK cells and by inhibiting the transcript of mRNA of perforin, granzyme A and granulysin. Taken together, these findings indicate that organophosphorus pesticides inhibited NK, LAK and CTL activities mediated at least by impairment of both the granule exocytosis and FasL/Fas pathways. We are grateful to Professor Krensky AM at Medical School of Stanford University for his helpful advice.

NK，LAK和CTL通过两种主要机制诱导肿瘤或病毒感染靶细胞的细胞死亡。第一个机制是通过胞吐作用直接释放含有穿孔蛋白，颗粒状和颗粒素的细胞溶剂颗粒以杀死靶细胞。第二种机制是由FAS配体（FAS-L）/FAS途径介导的。在当前的Syudy中，我们检查了一种二甲基2,2-二氯丙基磷酸二甲基（DDVP），农药对NK，CTL和Lak pko Mial in Vitro in Vitro fitro fitro fasive antivise antivise antivise antivise yacs yacs-cint sass-cints a的活性对NK，CTL和LAK活性的作用。我们发现DDVP以剂量依赖性方式显着降低了NK，CTL和LAK活性，并且PKO小鼠的CTL和LAK活性被抗FASL抗体显着阻断，这表明DDVP和抗FASL抗体具有相同/相似的抑制LAK和CTL活性的机制。我们进一步发现，DDVP分别以剂量依赖性的方式降低了YAC-1细胞上Fas抗原的表达，而FASL的表达分别降低了FASL的表达。综上所述，这些发现表明，DDVP诱导的PKO小鼠中NK，LAK和CTL活性的抑制是通过FASL/FAS途径的损害介导的。我们还发现，DDVP不仅显着抑制了颗粒状的活性，而且还降低了细胞内的穿孔蛋白，颗粒酶A和颗粒蛋白的细胞内水平，这是通过诱导NK细胞脱粒和抑制perforin，Granzyme A和Granulululysin和Granulululysin的mRNA的转录来介导的。综上所述，这些发现表明，有机磷农药抑制了NK，LAK和CTL活性，至少通过颗粒胞胞菌病和FASL/FAS途径损害而介导的介导的活性。我们感谢斯坦福大学医学院的Krensky AM教授的有益建议。

项目成果

Dimethyl 2,2-dichlorovinyl phosphate (DDVP) markedly inhibits activities of natural killer cells, cytotoxic T lymphocytes and lymphokine-activated killer cells via the Fas-ligand/Fas pathway in perform-knockout (PKO) mice.

二甲基 2,2-二氯乙烯基磷酸盐 (DDVP) 通过 Fas-配体/Fas 途径显着抑制执行基因敲除 (PKO) 小鼠中自然杀伤细胞、细胞毒性 T 淋巴细胞和淋巴因子激活的杀伤细胞的活性。

• 发表时间: 2004
• 期刊: Toxicology 204
• 作者: Li Q;Nakadai A;Takeda K. Kawada T.
• 通讯作者: Takeda K. Kawada T.

Dimethyl 2, 2-dichlorovinyl phosphate (DDVP) markedly decreases the expression of perform, granzyme A and granulysin in human NK-92CI cell line.

磷酸二甲酯 (DDVP) 显着降低人 NK-92CI 细胞系中 perper、颗粒酶 A 和颗粒溶素的表达。

• 发表时间: 2005
• 期刊: Toxicology 213(1-2)
• 作者: Li Q;Nakadai A;Ishizaki M;Morimoto K;Ueda A;Krensky AM;Kawada T.
• 通讯作者: Kawada T.

The new mechanism of organophosphorus pesticides-induced inhibition of cytolytic activity of killer cells.

有机磷农药抑制杀伤细胞溶细胞活性的新机制

• 发表时间: 2006
• 期刊: Cellular & Molecular Immunology (in press)
• 作者: Li Q;Kawada T.
• 通讯作者: Kawada T.