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3,4-Dichloropropionanilide (DCPA) inhibits T-cell activation by altering the intracellular calcium concentration following store depletion.
Lewis-TL; Brundage-KM; Brundage-RA; Barnett-JB
Toxicol Sci 2008 May; 103(1):97-107
Stimulation of T cells through the T-cell receptor results in the activation of a series of signaling pathways that leads to the secretion of interleukin (IL)-2 and cell proliferation. Influx of calcium (Ca2+) from the extracellular environment, following internal Ca2+ store depletion, provides the elevated and sustained intracellular calcium concentration ([Ca2+](i)) critical for optimal T-cell activation. Our laboratory has documented that exposure to the herbicide 3,4-dichloropropionanilide (DCPA) inhibits intracellular signaling events that have one or more Ca2+ dependent steps. Herein we report that DCPA attenuates the normal elevated and sustained [Ca2+](i) that follows internal store depletion in the human leukemic Jurkat T cell line and primary mouse T cells. DCPA did not alter the depletion of internal Ca2+ stores when stimulated by anti-CD3 or thapsigargin demonstrating that early inositol 1,4,5-triphosphate-mediated signaling and depletion of Ca2+ stores were unaffected. 2-Aminoethyldiphenol borate (2-APB) is known to alter the store-operated Ca2+ (SOC) influx that follows Ca2+ store depletion. Exposure of Jurkat cells to either DCPA or 50 mu M 2-APB attenuated the increase in [Ca2+](i) following thapsigargin or anti-CD3 induced store depletion in a similar manner. At low concentrations, 2-APB enhances SOC influx but this enhancement is abrogated in the presence of DCPA. This alteration in [Ca2+](i), when exposed to DCPA, significantly reduces nuclear levels of nuclear factor of activated T cells (NFAT) and IL-2 secretion. The plasma membrane polarization profile is not altered by DCPA exposure. Taken together, these data indicate that DCPA inhibits T-cell activation by altering Ca2+ homeostasis following store depletion.
Histopathology; Immunotoxins; Laboratory-animals; Animals; Animal-studies; Immune-reaction; Immune-system; Immune-system-disorders; Cell-biology; Cell-differentiation; Cell-function; Cell-metabolism; Cell-transformation; Cellular-reactions; Cellular-transport-mechanism; Hepatotoxicity; Herbicides
Rodney A. Brundage, W Virginia Univ, Sch Med, Dept Microbiol Immunol & Cell Biol, POB 9177, Morgantown, WV 26506 USA
Issue of Publication
Disease and Injury: Asthma and Chronic Obstructive Pulmonary Disease
WV; SC; NV
Page last reviewed: May 10, 2019
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