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 perforin-knockout (PKO) mice
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 perforin-knockout (PKO) mice
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DOI：
10.1016/j.tox.2004.05.019
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发表时间：
2004-11-01
期刊：
影响因子：
4.5
通讯作者：
Kawada, T
中科院分区：
文献类型：
--
作者：
Li, Q;Nakadai, A;Kawada, T
自然杀伤 (NK)、淋巴因子激活的杀伤 (LAK) 和细胞毒性 T 淋巴细胞 (CTL) 细胞通过两种主要机制诱导靶细胞死亡：穿孔素/颗粒酶途径和 Fas 配体 (FasL)/Fas 途径。我们之前发现有机磷农药显着抑制人和鼠的NK、LAK和CTL活性，并且这种抑制部分是由颗粒酶的抑制介导的。我们在这里通过使用穿孔素敲除 (PKO) 小鼠询问有机磷农药是否也会影响 FasL/Fas 通路。因此，我们在本研究中以 Fas 抗原阳性 YAC-1 细胞为靶点，在体外研究了有机磷农药 2,2-二氯乙烯磷酸二甲酯 (DDVP) 对 PKO 小鼠 NK、CTL 和 LAK 活性的影响。我们发现DDVP以剂量依赖性方式显着降低NK、CTL和LAK活性，并且抗FasL抗体显着阻断PKO小鼠的CTL和LAK活性，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 分别以剂量依赖性方式降低 YAC-1 细胞上 Fas 抗原的表达和 LAK 细胞上 FasL 的表达。综上所述，这些发现表明，DDVP 诱导的 PKO 小鼠 NK、LAK 和 CTL 活性抑制是由 FasL/Fas 通路损伤介导的。 (C) 2004 Elsevier Ireland Ltd. 保留所有权利。
Natural killer (NK), lymphokine-activated killer (LAK) and cytotoxic T lymphocyte (CTL) cells induce target cell death by two main mechanisms, the perforin/granzyme pathway and the Fas-ligand (FasL)/Fas pathway. We have previously found that organophosphorus pesticides significantly inhibit human and murine NK, LAK and CTL activities and that this inhibition is partially mediated by the inhibition of granzymes. We asked here whether organophosphorus pesticides also affect the FasL/Fas pathway by using perforin-knockout (PKO) mice. Thus, 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 in the present study. 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. (C) 2004 Elsevier Ireland Ltd. All rights reserved.