title: Organophosphorus pesticides markedly inhibit the activities of natural killer, cytotoxic T lymphocyte and lymphokine-activated killer: a proposed inhibiting mechanism via granzyme inhibition.
abstract: We have previously found that diisopropyl methylphosphonate, an organophosphorus by-product generated during sarin synthesis in the Tokyo sarin disaster, significantly inhibited natural killer (NK) and cytotoxic T lymphocyte (CTL) activities. In the present study, to investigate whether organophosphorus pesticides (OPs) also affect NK and CTL activities, we firstly examined the effect of five OPs on human NK activity, and then the effect of Dimethyl 2,2-dichlorovinyl phosphate (DDVP), an OP on murine splenic NK, CTL and lymphokine-activated killer (LAK), and human LAK activities in vitro. To explore the underlying mechanism of decreased NK activity, we also investigated the effect of 4-(2-aminoethyl) benzenesulfonyl fluoride-HCl (p-ABSF), an inhibitor of serine proteases on NK, LAK and CTL activities, and the effect of DDVP on the activity of granzymes (serine proteases). We found that OPs significantly decreased human NK activity in a dose-dependent manner, but the degree of decrease in NK activity differed among the OPs investigated, and that DDVP significantly decreased NK, LAK and CTL activities in a dose-dependent manner, but the degree of decrease in these activities differed. p-ABSF showed a similar inhibitory pattern to DDVP, and had an additive inhibitory effect with DDVP on NK, LAK and CTL activities. We also found that DDVP significantly inhibited granzyme activity in a dose-dependent manner. These findings indicate that OPs significantly decrease NK, LAK and CTL activities in vitro via granzyme inhibition.
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: Noriyuki
authors.initials: N
authors.lastname: Nagahara
authors.forename: Hidemi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Masayasu
authors.initials: M
authors.lastname: Minami
mesh_terms: D000818:Animals; D004006:Dichlorvos / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007306:Insecticides / Q000633:toxicity*; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects*; D007694:Killer Cells, Natural / Q000187:drug effects*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D012697:Serine Endopeptidases / Q000502:physiology*; D015842:Serine Proteinase Inhibitors / Q000633:toxicity*; D013379:Substrate Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects
chemical_list: D007306:Insecticides; D015842:Serine Proteinase Inhibitors; D004006:Dichlorvos; D012697:Serine Endopeptidases