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ToxSci Advance Access originally published online on April 26, 2006
Toxicological Sciences 2006 92(1):103-114; doi:10.1093/toxsci/kfj212
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Exposure to a Metabolite of the Environmental Toxicant, Trichloroethylene, Attenuates CD4+ T Cell Activation-Induced Cell Death by Metalloproteinase–Dependent FasL Shedding

Sarah J. Blossom*,{dagger},1 and Kathleen M. Gilbert*,{dagger}

* Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205; and {dagger} Arkansas Children's Hospital Research Institute, Little Rock, Arkansas 72202

Received February 17, 2006; accepted April 7, 2006

Long-term exposure to the environmental contaminant trichloroethylene (TCE) in drinking water has been shown to promote autoimmune disease in association with the expansion of activated CD4+ T cells. The effects of TCE on CD4+ T cells were linked in the present study to the ability of TCE metabolite, trichloroacetaldehyde hydrate (TCAH), to inhibit activation-induced cell death (AICD) in CD4+ T cells. TCAH attenuated AICD in CD4+ T cells by decreasing FasL (CD178) expression but not by altering Fas (CD95) expression or by interfering with Fas-signaling events following direct engagement of the Fas receptor. The TCAH-induced decrease in FasL expression did not appear to be mediated at the transcriptional level but was instead due to increased shedding of FasL from the surface of the CD4+ T cells. The ability of TCAH to cleave FasL and thereby decrease AICD appeared to be mediated by metalloproteinases and correlated with a TCAH-induced increase in matrix metalloproteinase-7. Thus, this study presents the novel finding that the environmental contaminant TCE works via its metabolite TCAH to attenuate AICD by increasing metalloproteinase activity that cleaves FasL from CD4+ T cells. This represents a mechanism by which an environmental trigger inhibits AICD in CD4+ T cells and may thereby promote CD4+ T cell–mediated autoimmune disease.

Key Words: apoptosis; autoimmunity; T cells; metalloproteinase; trichloroethylene.


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S. J. Blossom, J. C. Doss, and K. M. Gilbert
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