Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

THA (Tacrine), a drug used in the experimental therapy of dementia of Alzheimer's disease type, and whose biochemical site of action is believed to be the neural cholinesterase, is shown, for the first time, to be an immunosuppressant in vitro on normal human peripheral blood lymphocytes in microgram quantities. THA down-regulates non-MHC restricted natural killer (NK) cell activity without affecting the general viability of cells. This down-regulation can be demonstrated at all effector and target (K562) concentrations, in purified resting NK cells as well as in lymphokine (interleukin 2) activated killer cells in 3- or 16-h NK assays and in all the blood samples tested. Kinetic analysis shows that the Vmax (maximal cytotoxic potential) and Km of NK cell-mediated cytolysis are also attenuated. Single cell assays using agarose matrix reveal that THA moderately interferes with tumor target binding/recognition events and strongly abrogates the delivery of lethal hit, thus lowering the frequency of active killer cells among THA-treated lymphocytes. THA down-regulates NK cells upon direct interaction and does not require the help of non-NK cells. The THA sensitive site(s) on NK cells does not appear to be perturbed significantly either by their proliferative status or by membrane modulations that may be normally induced by interleukin 2. The in vitro immunomodulatory pharmacological properties of THA reveal that the biological site of action of THA extends to non-neural cells also. Such non-neural models may be helpful in exploring the pathophysiological neuroimmunomodulatory properties of THA at cellular and molecular levels.
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PMID:Immunomodulation by 9-amino-1,2,3,4-tetrahydroacridine (THA): 1. Down-regulation of natural cell-mediated cytotoxicity in vitro. 176 1

The main toxicity of organophosphorus pesticides (OPs) is neurotoxicity, which is caused by the inhibition of acetylcholinesterase. OPs also affect immune responses including effects on antibody production, IL-2 production, T cell proliferation, decrease of CD5 cells, and increase of CD26 cells and autoantibodies. However, there have been few papers investigating the mechanism of OP-induced inhibition of cytolytic activity of killer cells. This study reviews the new mechanism of OP-induced inhibition of activities of natural killer (NK), lymphokine-activated killer (LAK) and cytotoxic T lymphocytes (CTL). 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, which is called the granule exocytosis pathway. The second mechanism is mediated by the Fas ligand (Fas-L)/Fas pathway. To date, it has been reported that OPs inhibit NK, LAK and CTL activities by at least the following three mechanisms: 1) OPs impair the granule exocytosis pathway of NK, LAK and CTL cells by inhibiting the activity of granzymes, and by decreasing 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; 2) OPs impair the FasL/Fas pathway of NK, LAK and CTL cells, 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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PMID:The mechanism of organophosphorus pesticide-induced inhibition of cytolytic activity of killer cells. 1689 97

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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PMID:New mechanism of organophosphorus pesticide-induced immunotoxicity. 1750 86