circ_0000638 inhibits neodymium oxide-induced bronchial epithelial cell inflammation through the miR-498–5p/NF-κB axis
Introduction
With the widespread application of rare earth (RE) in industry and people's lives, people are increasingly being exposed to rare earth elements. The impact of the elements on the ecological environment and human health has aroused concerns. In China, about 5200 tons of RE were released into cultivated soils in 2002 in the form of fertilizers (Zhuang et al., 2017a). Furthermore, large-scale exploitation of RE has resulted in a remarkable increase in environmental pollution around mining areas (Mao et al., 2011; Olias et al., 2005). An estimated 119,000 tons of rare earth oxides have entered the soil due to mining activities in China (Huang et al., 2007). For these reasons, increased attention is being given to RE exposure and bioaccumulation, as well as its health-related effects on humans and wildlife. Neodymium (Nd) is a light rare earth element and widely used in agriculture, animal husbandry, laser materials, magnetic materials, etc., and its safety issues are receiving increased attention. Studies have shown that exposure to neodymium oxide particles through the respiratory tract can cause various respiratory diseases, such as lung tissue inflammation (Kim et al., 2017). Our previous studies found that neodymium oxide particles can cause inflammation in rat lungs and activate the NF-κB and caspase-3 signaling pathways in rat alveolar macrophage NR8383 cells, as well as promote the synthesis and release of inflammatory chemokines (Huang et al., 2017). However, the mechanism of neodymium oxide-induced lung injury is still unclear and lacks evidence of early molecular regulation.
CircRNA is a class of RNA with a covalently closed circular structure without 5′ and 3′ sticky ends. CircRNA is not easily degraded by exonucleases, so the structure is more stable than linear RNA. Existing studies have shown that circRNA has many biological functions, including post-transcriptional regulation, gene transcriptional regulation, and protein translation (X. Cai et al., 2019, 2018; Zhou et al., 2018; Du et al., 2017). More and more studies have indicated that circRNA is associated with the development and progression of various diseases, including cardiovascular diseases, Alzheimer's disease, and cancer (Li et al., 2018a, c; Li et al., 2019a; Lu et al., 2019). It has been found that circRNA participates in the regulation of a variety of important biological processes, such as autophagy, oxidative stress, and inflammation. For instance, circARF3 is involved in the regulation of adipose tissue inflammation, which is mediated by the NF-κB signaling pathway (Zhang et al., 2019). Circular RNA ciRS-7 can trigger the migration and invasion of esophageal squamous cell carcinoma cells via miR-7/KLF4 and NF-κB (Huang et al., 2018). The NF-κB signaling pathway is a classical inflammatory signaling pathway that mediates multiple biological processes, including proliferation, apoptosis, and inflammation (Zhang et al., 2019; Normand et al., 2018). Studies have found that the NF-κB pathway plays an important role in the development of lung diseases, including asthma, pneumoconiosis, pulmonary fibrosis, and lung cancer (T. Cai et al., 2019; Qiu et al., 2019). Our previous study showed that NF-κB is activated in neodymium oxide-treated rat lung macrophages (Huang et al., 2017). In this study, we constructed a cellular inflammatory model by inducing 16HBE cells using neodymium oxide particles and explored the role and mechanism of circ_0000638 in neodymium oxide-induced 16HBE cell inflammation. We found that circ_0000638 was significantly downregulated in neodymium oxide-treated 16HBE cells. We further studied associated mechanisms and found that circ_0000638 competitively bound to miR-498–5p to inhibit NF-κB activation and downregulated the expression of inflammatory factors IL-8 and IL-1β in treated 16HBE cells.
Section snippets
Cell culture
The human bronchial epithelial cell line 16HBE and human embryonic kidney 293-T cells were kindly provided by the Environmental Carcinogenic Research Institute of the State Key Laboratory of Respiratory Diseases, Guangzhou Medical University (Guangzhou, China). The 16HBE cells were cultured in Modified Eagle Medium (MEM; HyClone, Logan, UT, USA) containing 10% fetal bovine serum (Sijiqing Corporation, Hangzhou, China). The 293-T cells were cultured in Dulbecco's Modified Eagle Medium (DMEM;
Neodymium oxide promotes IL-8 and IL-1β expression in 16HBE cells
Because epithelial cells are the primary target cells of environmental chemical toxic substances, we chose the human bronchial epithelial 16HBE cells to explore the cytotoxic effects of neodymium oxide. First, after treating 16HBE cells with different doses of neodymium oxide for 24 h and 48 h, we found that the survival rates of the cells treated with 40 μg/mL, 60 μg/mL, 80 μg/mL, 100 μg/mL, and 120 μg/mL of neodymium oxide were decreased (Fig. 1A). We next detected the inflammatory factors
Discussion
Neodymium is an important light rare earth element, existing mainly in the form of neodymium oxide. It is used in the production of glass, ceramics, alloy materials, strong magnets, rubber products, and medical products, amongst others. With the large-scale exploitation and application, neodymium-related environmental pollution and health hazards have become increasingly prominent. We had performed experiments for the characterization of neodymium oxide particles in our previous report (Hua et
Conclusions
The present study demonstrated that neodymium oxide caused an inflammatory response in 16HBE cells. Circ_0000638 modestly downregulated the expression of IL-8 and IL-1β in neodymium oxide-treated 16HBE cells. Upon exploring the mechanism of circ_0000638, our results have shown that circ_0000638 can inhibit NF-κB activation by competitively binding to miR-498–5p, further downregulating the expressions of IL-8 and IL-1β in neodymium oxide-treated 16HBE cells. The present study provides a clue for
CRediT authorship contribution statement
Hainan Xue: Conceptualization, Methodology, Validation, Investigation, Data curation, Writing - original draft, Visualization. Feng Yu: Conceptualization, Methodology, Validation. Xia Zhang: Conceptualization, Formal analysis. Ling Liu: Methodology, Validation. Lihua Huang: Resources, Writing - review & editing, Project administration, Funding acquisition.
Declaration of competing interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Acknowledgments
The National Natural Science Foundation of China (81960596, 81760600); the Inner Mongolia Higher Education Institute “Youth Talents Science and Technology Support Program” (Class A, NJYT-19-A16); and the Inner Mongolia Autonomous Region Higher Education Research Project (NJZY17252). Natural Science Foundation of Inner Mongolia (2019MS08057).
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