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J Nippon Med Sch. 2007 Apr;74(2):92-105.

New mechanism of organophosphorus pesticide-induced immunotoxicity.

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Department of Environmental Medicine, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.


Organophosphorus pesticides (OPs) are widely used throughout the world as insecticides in agriculture and as eradicating agents for termites around homes. The main toxicity of OPs is neurotoxicity, which is caused by the inhibition of acetylcholinesterase. OPs also affect the immune response, including effects on antibody production, interleukin-2 production, T cell proliferation, decrease of CD5 cells, and increases of CD26 cells and autoantibodies, Th1/Th2 cytokine profiles, and the inhibition of natural killer (NK) cell, lymphokine-activated killer (LAK) cell, and cytotoxic T lymphocyte (CTL) activities. However, there have been few studies of the mechanism of OP-induced immunotoxicity, especially the mechanism of OP-induced inhibition of cytolytic activity of killer cells. This study reviews new mechanisms of OP-induced inhibition of the activities of NK cells, LAK cells, and CTLs. It has been reported that NK cells, LAK cells, and CTLs induce cell death in tumors or virus-infected target cells by two main mechanisms. The first mechanism is direct release of cytolytic granules that contain the pore-forming protein perforin, several serine proteases termed granzymes, and granulysin by exocytosis to kill target cells, which is called the granule exocytosis pathway. The second mechanism is mediated by the Fas ligand (Fas-L)/Fas pathway, in which FasL (CD95 L), a surface membrane ligand of the killer cell cross links with the target cell's surface death receptor Fas (CD95) to induce apoptosis of the target cells. To date, it has been reported that OPs inhibit NK cell, LAK cell, and CTL activities by at least the following three mechanisms: 1) OPs impair the granule exocytosis pathway of NK cells, LAK cells, and CTLs by inhibiting the activity of granzymes, and by decreasing the intracellular levels of perforin, granzyme A, and granulysin, which were mediated by inducing degranulation of NK cells and by inhibiting the transcription of the mRNAs of perforin, granzyme A, and granulysin. 2) OPs impair the FasL/Fas pathway of NK cells, LAK cells, and CTLs, as investigated by using perforin-knockout mice, in which the granule exocytosis pathway of NK cells does not function and only the FasL/Fas pathway remains functional. 3) OPs induce apoptosis of immune cells.

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