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ToxSci Advance Access published online on February 14, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn031
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Published by Oxford University Press 2008.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.

3,4-Dichloropropionanilide (DCPA) Inhibits T Cell Activation by Altering the Intracellular Calcium Concentration Following Store Depletion1

Tricia L. Lewis*,{dagger}, Kathleen M. Brundage*,{dagger}, Rodney A. Brundage2,{ddagger} and John B. Barnett*,{dagger}

* Department of Microbiology, Immunology and Cell Biology {dagger} Center for Immunopathology and Microbial Pathogenesis, West Virginia University School of Medicine, Morgantown, WV 26506 {ddagger} National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, Morgantown, WV 26506

Correspondence to: John B. Barnett, Ph.D., Department of Microbiology, Immunology and Cell Biology, PO Box 9177, West Virginia University, Morgantown, WV. 26506-9177, (T). 304-293-4029; (F) 304-293-7823, jbarnett{at}hsc.wvu.edu

Received December 17, 2007; revision received February 6, 2008; accepted February 10, 2008


  Abstract

Stimulation of T cells through the T cell receptor (TCR) results in the activation of a series of signaling pathways that leads to the secretion of 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 IP3-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 µM 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 NFAT levels 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.

Key Words: T Cells; Signal Transduction; Calcium; 3,4-dichloropropionanilide; propanil.

1 The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health

2 Present address: Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26506.


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