Organophosphorous pesticide metabolite (DEDTP) induces changes in the activation status of human lymphocytes by modulating the interleukin 2 receptor signal transduction pathway.
Diethyldithiophosphate (DEDTP) is a metabolite formed by biotransformation of organophosphorous (OP) compounds that has a longer half-life than its parental compound. Here we evaluate the effects of DEDTP on human CD4+ T lymphocytes. In vitro exposure to DEDTP (1-50μM) decreased [(3)H]thymidine incorporation in resting cells and increased CD25 surface expression without altering cell viability. DEDTP treatment inhibited anti-CD3/anti-CD28 stimulation-induced CD4+ and CD8+ T cell proliferation determined by CFSE dilution. Decreased CD25 expression and intracellular IL-2 levels were correlated with this defect in cell proliferation. IL-2, IFN-γ and IL-10 secretion were also reduced while IL-4 secretion was not altered. Increased phosphorylation of SOCS3 and dephosphorylation of STAT5 were induced by DEDTP after as little as 5min of exposure. In addition, DEDTP induced phosphorylation of ERK, JNK and p38 and NFAT nuclear translocation. These results suggest that DEDTP can modulate phosphorylation of intracellular proteins such as SOCS3, which functions as a negative regulator of cytokine signalling, and that DEDTP exposure may thus cause T cells to fail to respond to further antigen challenges.
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Toxicology Department, Centro de Investigación y de Estudios Avanzados-IPN, Av. IPN 2508, San Pedro Zacatenco, Mexico City 07360, Mexico.
Barrera
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Ortega
A
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Vega
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D018106:CD28 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D063086:Organothiophosphates / Q000378:metabolism / Q000633:toxicity*; D010575:Pesticides / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
D018106:CD28 Antigens; D016207:Cytokines; D053645:Interleukin-2 Receptor alpha Subunit; D063086:Organothiophosphates; D010575:Pesticides; D015375:Receptors, Interleukin-2; C106644:SOCS3 protein, human; D050799:STAT5 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins