ABSTRACT

o,p’-Dichlorodiphenyltrichloroethane (o,p’-DDT) is a representative endocrine disruptor, and exposure to o,p’-DDT may produce immune disorders and inflammation, leading to various diseases such as cancer. Chronic airway inflammation is characterized by excessive mucus secretion resulting in chronic obstructive pulmonary disease (COPD). Mucin 5AC (MUC5AC), one of the mucus genes, plays an important role in mucus secretion and inflammation in the airways. The aim of this study was to examine the effects of o,p′-DDT on the regulation of MUC5AC expression in human lung epithelial A549 cell line. o,p′-DDT increased mRNA levels and the promoter activity of MUC5AC. Transient transfection with mutation promoter constructs of MUC5AC demonstrated that nuclear factor kappa-b (NF-κB) and activator protein 1(AP-1) response elements were essential for the consequences of o,p’-DDT on MUC5AC expression. In addition, o,p′-DDT induced phosphorylation of ERK, JNK, p38, and Akt, which are involved in the regulation of MUC5AC expression. It is noteworthy that inhibitors of NF-κB, AP-1, Akt, and MAPKs blocked enhanced o,p′-DDT-induced MUC5AC mRNA expression. Data indicate that o,p′-DDT increase in NF-κB, and AP-1 transcriptional activation-dependent MUC5AC expression is associated with stimulation of Akt and MAPK signaling pathways in A549 cells.

摘要

o,p'-二氯二苯基三氯乙烷（o,p' -DDT）是一种代表性的内分泌干扰物，接触o,p' -DDT可能会产生免疫紊乱和炎症，导致癌症等多种疾病。慢性气道炎症的特征是粘液分泌过多，导致慢性阻塞性肺疾病 (COPD)。粘蛋白 5AC (MUC5AC) 是粘液基因之一，在气道粘液分泌和炎症中起重要作用。本研究的目的是检查o,p '-DDT 对调节人肺上皮 A549 细胞系中 MUC5AC 表达的影响。o,p'-DDT 增加了 MUC5AC 的 mRNA 水平和启动子活性。用 MUC5AC 突变启动子构建体的瞬时转染表明，核因子 kappa-b (NF-κB) 和激活蛋白 1(AP-1) 响应元件对于o,p' -DDT 对 MUC5AC 表达的影响至关重要。此外，o,p' -DDT 诱导 ERK、JNK、p38 和 Akt 的磷酸化，这些都参与 MUC5AC 表达的调节。值得注意的是，NF-κB、AP-1、Akt 和 MAPKs 的抑制剂阻断了增强的o,p '-DDT 诱导的 MUC5AC mRNA 表达。数据表明o,pNF-κB 中的 '-DDT 增加和 AP-1 转录激活依赖性 MUC5AC 表达与 A549 细胞中 Akt 和 MAPK 信号通路的刺激有关。