Effect of trichloroacetaldehyde on the activation of CD4+T cells in occupational medicamentosa-like dermatitis: An in vivo and in vitro study
Effect of trichloroacetaldehyde on the activation of CD4+T cells in occupational medicamentosa-like dermatitis: An in vivo and in vitro study
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三氯乙醛对职业性药物样皮炎 CD4( )T 细胞活化的影响：一项体内外研究
DOI：
10.1016/j.tox.2019.05.014
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发表时间：
2019-07-01
期刊：
影响因子：
4.5
通讯作者：
Zhuang, Zhixiong
中科院分区：
文献类型：
--
作者：
Li, Wenxue;Liu, Xiaoling;Zhuang, Zhixiong
三氯乙烯所致的职业性药疹样皮炎是一种自身免疫性肝损伤的过敏性疾病，日益成为中国严重的职业健康问题。然而，OMLDT的发病机制仍不明确。在这项研究中，30名三氯乙烯诱导的OMLDT患者、58名暴露对照组和40名非暴露对照组被纳入研究。结果显示，与暴露组和非暴露组相比，OMLDT患者外周血中活化的CD_4~(+)T细胞比例显著升高(CD_(62)L下调)，提示CD_4~(+)T细胞的激活是OMLDT发病过程中的一个关键细胞事件。同时，OMLDT患者外周血中IL-2、干扰素-γ、肿瘤坏死因子-α和IL-17A等细胞因子的表达明显增加，而IL-4的表达明显降低。在体外实验中，我们发现三氯乙烯代谢产物三氯乙醛(TCAH)，而不是三氯乙酸(TCA)或三氯乙醇(TCOH)可以激活以细胞内钙升高为特征的初始CD_4(+)T细胞，下调CD_(62)L，从而触发IL-2、干扰素-γ和肿瘤坏死因子-α的分泌。值得注意的是，在OMLDT患者中，NF-kappa B和p38MAPK的磷酸化状态升高。此外，TCAH还可激活p38MAPK和核因子-kappaB，提示p38MAPK和核因子-kappaB通路在CD4(+)T细胞活化中的作用。此外，我们还发现，抑制Schiff碱的形成降低了TCAH诱导NAVE CD4(+)T细胞活化和p38MAPK和NF-kappa B通路的能力。综上所述，我们发现OMLDT患者外周血中CD4(+)T细胞的活化和IL-2、干扰素-γ、肿瘤坏死因子-α等细胞因子的升高和IL-4的降低与OMLDT的发生有关。TCAH可通过Schiff碱诱导的核因子-kappaB和p38MAPK的激活激活原始的CD4(+)T细胞，这可能参与了OMLDT的发生发展。这些发现为OMLDT的发病机制提供了新的见解。
Occupational medicamentosa-like dermatitis induced by trichloroethylene (OMLDT) is a hypersensitivity disease with autoimmune liver injury, which has increasingly become a serious occupational health problem in China. However, the pathogenesis of OMLDT remained undefined. In this study, 30 TCE-induced OMLDT patients, 58 exposure controls, and 40 non-exposure controls were recruited. We showed that the ratio of activated CD4(+) T cells (downregulation of CD62 L) was dramatically increased in OMLDT patients compared to exposure and non exposure control, suggesting that CD4(+) T cells activation was a key cellular event in the development of OMLDT. In parallel, the expression of cytokine including IL-2, IFN-gamma, TNF-alpha and IL-17A were increased obviously and IL-4 decreased in CD4(+) T cells from OMLDT patients. in vitro assay, we found that trichloroethylene metabolites trichloroacetaldehyde (TCAH), not trichloroacetic acid (TCA) or Trichloroethanol (TCOH) could activate the na ve CD4(+)T cells characterized by a rise in intracellular calcium, down-regulated CD62 L and subsequently trigger the secretion of IL-2, IFN-gamma and TNF-alpha. Notably, the phosphorylation status of NF-kappa B and p38MAPK were elevated in OMLDT patients. Moreover, TCAH also could activate the p38MAPK and NF-kappa B, suggesting the role of p38MAPK and NF-kappa B pathways in the activation of CD4(+) T cells. In addition, we found that the inhibition of Schiff base formation decreased the ability of TCAH to induce the activation of na ve CD4(+)T cells and p38MAPK and NF-kappa B pathway. In conclusion, we revealed that the CD4(+)T activation and increased the cytokines including IL-2, IFN-gamma and TNF-alpha but decreased IL-4 in CD4(+)T cells were associated with OMLDT. TCAH could activate na ve CD4(+)T cells through NF-kappa B and p38MAPK activation induced by Schiff base formation, which might contribute to the development of OMLDT. These findings provide a new insight into the pathogenesis of OMLDT.