Abstract
CC16 is almost exclusively expressed in non-ciliated epithelial Clara cells, and widely used as a Clara cell marker. Diesel exhaust particles (DEPs), the fine particulate matters produced by diesel engines, cause or exacerbate airway-related diseases. Our previous study documented that DEP inhibits the CC16 expression in the immortalized mouse Clara cell line through methylation of C/EBPα promoter. However, the molecular mechanism by which DEP regulates CC16 secretion is unclear. Here, we isolated CC16 containing Clara cells (CC16+) from human distal lung, and found that DEP inhibited CC16 secretion from CC16+ cells via methylation of C/EBPα and inhibition of Munc18b transcription. CC16+ cell conditioned media containing different concentrations of CC16 was prepared and used for culture of airway epithelial cells BEAS-2B with no expression of CC16. A positive correlation was observed between CC16 level and DEP-induced autophagy activity, and a negative correlation between CC16 level and DEP-induced pro-inflammatory cytokine TNF-α, IL-6, and IL-8 level, suggesting that CC16 might mitigate DEP-induced inflammation via promoting autophagy in BEAS-2B cells. This result was further confirmed by adding recombinant CC16 to BEAS-2B cells exposed to DEP. Moreover, CC16 level was significantly increased when CC16+ cells were cultured in BEAS-2B cell conditioned medium containing TNF-α or the normal medium supplemented with recombinant TNF-α, suggesting that TNF-α induced CC16 production and secretion from CC16+ cells. Collectively, these data point that CC16 and TNF-α form a negative feedback loop, and this negative feedback loop between Clara cells and normal airway epithelial cells protects against DEP exposure-induced inflammation.
Highlights
Accumulating epidemiological, laboratory and clinical studies demonstrate that exposure to increased level of particulate matter (PM) is related to the increased morbidity and mortality of multiple human diseases, such as allergic disorders, respiratory diseases, cardiac diseases, and renal diseases [1,2,3,4]
Single cell suspensions were prepared by human distant normal lung tissues where Clara cells are located, and CC16+ and CC16- cells were sorted directly by Fluorescence-activated cell sorting (FACS)
The results showed that all cells in the CC16+ sorted fraction expressed pan-keratin (Figure 1D)
Summary
Accumulating epidemiological, laboratory and clinical studies demonstrate that exposure to increased level of particulate matter (PM) is related to the increased morbidity and mortality of multiple human diseases, such as allergic disorders, respiratory diseases, cardiac diseases, and renal diseases [1,2,3,4]. With the development of the economy, logistics based on the transportation industry has become a major service industry in the modern national economy. Diesel engines are predominantly used due to high efficiency and low cost. Diesel exhaust particles (DEPs), the fine particulate matters produced by diesel engines, are one of the major parts of PM2.5. There is growing evidence that DEPs induce or exacerbate the diseases involving the airway, such as www.aging-us.com pulmonary arterial hypertension, asthma, and chronic obstructive pulmonary disease (COPD) [7,8,9]
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