Abstract
Apart from its role in the metabolism of carcinogens, the aryl hydrocarbon receptor (AhR) has been suggested to be involved in the control of inflammatory responses within the respiratory tract. However, the mechanisms responsible for this are only partially known. In this study, we used A549 cell line, as a human model of lung alveolar type II (ATII)-like cells, to study the functional role of the AhR in control of inflammatory responses. Using IL-1β as an inflammation inducer, we found that the induction of cyclooxygenase-2 and secretion of prostaglandins, as well as expression and release of pro-inflammatory cytokines, were significantly higher in the AhR-deficient A549 cells. This was linked with an increased nuclear factor-κB (NF-κB) activity, and significantly enhanced phosphorylation of its regulators, IKKα/β, and their target IκBα, in the AhR-deficient A549 cells. In line with this, when we mimicked the exposure to a complex mixture of airborne pollutants, using an organic extract of reference diesel exhaust particle mixture, an exacerbated inflammatory response was observed in the AhR-deficient cells, as compared with wild-type A549 cells. Together, the present results indicate that the AhR may act as a negative regulator of the inflammatory response in the A549 model, via a direct modulation of NF-κB signaling. Its role(s) in the control of inflammation within the lung alveoli exposed to airborne pollutants, especially those which simultaneously activate the AhR, thus deserve further attention.
Highlights
The lung is continuously exposed to airborne environmental agents present in the atmosphere and its epithelial cell population plays a major role in recognizing potential stressors [1], contributing to the maintenance of lung homeostasis [2]
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We found that levels of phosphorylated IKKα/β kinases and their target, inhibitor of NF-kB α (IκBα), were higher in the AhR-knockout cell variants (AhR KO) cells, as compared with the AhR withilcdo-nttyrpolewcieldll-sty(pWe Tce)lls (WT) cells (Figure 5B)
Summary
The lung is continuously exposed to airborne environmental agents present in the atmosphere and its epithelial cell population plays a major role in recognizing potential stressors [1], contributing to the maintenance of lung homeostasis [2]. The aryl hydrocarbon receptor (AhR) is a highly conserved ligand-activated transcription factor that is expressed in most human tissues, including alveolar epithelium [9]. A recent study has reported that anti-inflammatory action of the AhR could be independent of its binding to dioxin-responsive elements (DRE) [22]. Together, these data suggest that the AhR might interfere with the NF-κB signaling in respiratory system through multiple mechanisms. These data suggest that the AhR might interfere with the NF-κB signaling in respiratory system through multiple mechanisms It is presently not clear if the attenuation of NF-κB activity is relevant for the AhR action within the context of ATII-like cells
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