Center for Health and the Environment, University of California, Davis 95616, California.
Program of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-8521, Japan.
Toxicol Sci. 2019 Aug 1;170(2):404-414. doi: 10.1093/toxsci/kfz114.
Polycyclic aromatic hydrocarbons (PAHs) contained in airborne particulate matter have been identified as a contributing factor for inflammation in the respiratory tract. Recently, interleukin-33 (IL-33) is strongly suggested to be associated with airway inflammation. Aryl hydrocarbon receptor (AhR) is a receptor for PAHs to regulate several metabolic enzymes, but the relationships between AhR and airway inflammation are still unclear. In this study, we examined the role of AhR in the expression of IL-33 in macrophages. THP-1 macrophages mainly expressed IL-33 variant 5, which in turn was strongly induced by the AhR agonists 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) and kynurenine (KYN). AhR antagonist CH223191 suppressed the increase in IL-33 expression. Promoter analysis revealed that the IL-33 promoter has 2 dioxin response elements (DREs). AhR was recruited to both DREs after treatment with TCDD or KYN as assessed by gel shift and chromatin immunoprecipitation assays. A luciferase assay showed that one of the DREs was functional and involved in the expression of IL-33. Macrophages isolated from AhR-null mice expressed only low levels of IL-33 even in response to treatment with AhR ligands compared with wild-type cells. The treatment of THP-1 macrophages with diesel particulate matter and particle extracts increased the mRNA and protein expression of IL-33. Taken together, the results show that ligand-activated AhR mediates the induction of IL-33 in macrophages via a DRE located in the IL-33 promoter region. AhR-mediated IL-33 induction could be involved in the exacerbation and/or prolongation of airway inflammation elicited by toxic chemical substances.
多环芳烃（PAHs）存在于空气中的颗粒物中，被认为是引起呼吸道炎症的一个因素。最近，白细胞介素-33（IL-33）强烈提示与气道炎症有关。芳烃受体（AhR）是 PAHs 的受体，可调节几种代谢酶，但 AhR 与气道炎症之间的关系尚不清楚。在这项研究中，我们研究了 AhR 在巨噬细胞中 IL-33 表达中的作用。THP-1 巨噬细胞主要表达 IL-33 变体 5，而 AhR 激动剂 2,3,7,8-四氯二苯并-p-二恶英（TCDD）和犬尿氨酸（KYN）强烈诱导其表达。AhR 拮抗剂 CH223191 抑制了 IL-33 表达的增加。启动子分析表明，IL-33 启动子有 2 个二恶英反应元件（DREs）。用 TCDD 或 KYN 处理后，通过凝胶迁移和染色质免疫沉淀分析，AhR 被募集到两个 DRE 上。荧光素酶报告基因检测表明，其中一个 DRE 是功能性的，参与了 IL-33 的表达。与野生型细胞相比，从 AhR 敲除小鼠中分离的巨噬细胞即使在接受 AhR 配体处理后，也仅表达低水平的 IL-33。用柴油机颗粒物和颗粒提取物处理 THP-1 巨噬细胞增加了 IL-33 的 mRNA 和蛋白表达。总之，这些结果表明，配体激活的 AhR 通过位于 IL-33 启动子区域的 DRE 介导巨噬细胞中 IL-33 的诱导。AhR 介导的 IL-33 诱导可能参与了有毒化学物质引起的气道炎症的恶化和/或延长。
