Exposure to a metabolite of the environmental toxicant, trichloroethylene, attenuates CD4+ T cell activation-induced cell death by metalloproteinase-dependent FasL shedding.
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.
Blossom
Sarah J
SJ
Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. blossomsarah@uams.edu
Gilbert
Kathleen M
KM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D017931:DNA Primers; D004785:Environmental Pollutants / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein; D005260:Female; D008213:Lymphocyte Activation / Q000187:drug effects*; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014241:Trichloroethylene / Q000633:toxicity*; D048069:Tumor Necrosis Factors / Q000378:metabolism*
D017931:DNA Primers; D004785:Environmental Pollutants; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D048069:Tumor Necrosis Factors; D014241:Trichloroethylene; D020783:Matrix Metalloproteinase 7