Induction of apoptosis in human lymphocytes by the herbicide 2,4-dichlorophenoxyacetic acid.
Dimethylammonium salt of 2,4-dichlorophenoxyacetic acid (DMA-2,4-D) is a widely used herbicide that is considered moderately toxic. In the present study we found that DMA-2,4-D is able to cause apoptosis in peripheral blood lymphocytes of healthy individuals and Jurkat T cells. Apoptosis induced by DMA-2,4-D was dose and time dependent, independent of Fas, TNF receptor 1 or the aromatic hydrocarbon receptor, and involved disruption of the mitochondrial transmembrane potential and activation of caspase-9. ZVAD-FMK, a broad-spectrum inhibitor of caspases, blocked DMA-2,4-D-induced apoptosis completely. While an inhibitor of caspase-9, as well as caspase-9 and caspase-3 inhibitors in combination, strongly blocked DMA-2,4-D-induced apoptosis, an inhibitor of caspase-3 had a moderate inhibitory effect. Unlike Fas-mediated apoptosis, the initiator caspase, caspase-8, was not involved in DMA-2,4-D-induced apoptosis. Transfection of Jurkat cells with Bcl-2 prevented DMA-2,4-D-induced disruption of the mitochondrial transmembrane potential and led to a complete blockage of apoptosis. Our data indicate that DMA-2,4-D kills human lymphocytes by initiating apoptosis via a direct effect on mitochondria. The activation of caspases occurs downstream of mitochondrial damage, and the dysfunction of mitochondria appears to be sufficient for triggering all downstream events leading to apoptosis.
Kaioumova
D
D
Department of Transplant Immunology, Institute of Immunology, University of Heidelberg, Heidelberg, Germany. dinara_kaioumova@med.uni-heidelberg.de
Süsal
C
C
Opelz
G
G
D015084:2,4-Dichlorophenoxyacetic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D001571:Benzoflavones / Q000494:pharmacology; D020169:Caspases / Q000502:physiology; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D006540:Herbicides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D008214:Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000276:immunology; D008928:Mitochondria / Q000187:drug effects / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology; D047888:Receptors, Tumor Necrosis Factor, Type I; D014162:Transfection; D019014:fas Receptor / Q000276:immunology
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD; D001571:Benzoflavones; D006540:Herbicides; D019253:Proto-Oncogene Proteins c-bcl-2; D018336:Receptors, Aryl Hydrocarbon; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C411023:anti-Fas monoclonal antibody; D019014:fas Receptor; D015084:2,4-Dichlorophenoxyacetic Acid; C011512:alpha-naphthoflavone; D020169:Caspases