代谢
长期暴露于饮用水中的一种环境污染物，三氯乙烯（TCE），已被证明能够促进与活化的CD4+ T细胞的扩增相关的自身免疫疾病。目前的研究将TCE对CD4+ T细胞的影响与TCE代谢物，三氯乙醛水合物（TCAH）能够抑制CD4+ T细胞中的活化诱导细胞死亡（AICD）的能力联系起来。TCAH通过减少FasL（CD178）的表达，而不是通过改变Fas（CD95）的表达，或通过干扰Fas受体直接结合后的Fas信号事件，来减弱CD4+ T细胞中的AICD。TCAH诱导的FasL表达减少似乎不是在转录水平上介导的，而是由于CD4+ T细胞表面FasL的脱落增加。TCAH能够裂解FasL并因此减少AICD的能力似乎是由金属蛋白酶介导的，并且与TCAH诱导的基质金属蛋白酶-7的增加相关。因此，本研究提出了一个新颖的发现，即环境污染物TCE通过其代谢物TCAH增加金属蛋白酶活性，从而通过从CD4+ T细胞中裂解FasL来减弱AICD。这代表了一种环境触发因素抑制CD4+ T细胞中AICD的机制，并可能因此促进CD4+ T细胞介导的自身免疫疾病。
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.
来源:Hazardous Substances Data Bank (HSDB)
