title: 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.
abstract: 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.
authors.affiliation: Department of Hygiene and Public Health, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan. qing-li@nms.ac.jp
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Ari
authors.initials: A
authors.lastname: Nakadai
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kawada
mesh_terms: D000818:Animals; D002460:Cell Line; D003864:Depression, Chemical; D004006:Dichlorvos / Q000633:toxicity*; D053222:Fas Ligand Protein; D007306:Insecticides / Q000633:toxicity*; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects; D007694:Killer Cells, Natural / Q000187:drug effects*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013154:Spleen / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects*; D019014:fas Receptor / Q000096:biosynthesis / Q000502:physiology*
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007306:Insecticides; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D019014:fas Receptor; D054353:Perforin; D004006:Dichlorvos