Aryl Hydrocarbon Receptor (AhR) Limits the Inflammatory Responses in Human Lung Adenocarcinoma A549 Cells via Interference with NF-κB Signaling

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.

Protective Effect of Eurotium cristatum Fermented Loose Dark Tea and Eurotium cristatum Particle on MAPK and PXR/AhR Signaling Pathways Induced by Electronic Cigarette Exposure in Mice

“…ticipate in a variety of cellular functions such as the regulation of the immune system and the suppression of the inflammatory response [48][49][50]. The experimental results of the PXR/AhR signaling pathway are indeed consistent with the reported results and a negative trend was observed between PXR/AhR and the level of inflammation (Figure 9).…”

“…Related studies have reported that the AhR binding site is very close to or overlaps with the NF-κB binding site, which suggests that AhR and NF-κB may have potential intermodulation and crosstalk effects [ 47 ]. Experimental studies in animal models of various inflammatory diseases have demonstrated that activation of AhR can participate in a variety of cellular functions such as the regulation of the immune system and the suppression of the inflammatory response [ 48 , 49 , 50 ]. The experimental results of the PXR/AhR signaling pathway are indeed consistent with the reported results and a negative trend was observed between PXR/AhR and the level of inflammation ( Figure 9 ).…”

From Nucleus to Organs: Insights of Aryl Hydrocarbon Receptor Molecular Mechanisms

“…In fact, it has been revealed the ability of AHR to suppress NF-κβ/p65 signaling pathway in intestinal epithelium [ 85 ]. Interestingly, a similar pattern was found in a model of inflammatory response in lung, where AHR presented a negative regulatory capacity of such response through direct modulation of NF-κβ signaling [ 86 ]. Additionally, this association of AHR with RelA has been found to activate NF-κβ activity in order to upregulate interleukin-6 (IL-6) expression [ 87 ].…”

Particulate matter 2.5 induces the skin barrier dysfunction and cutaneous inflammation via AhR‐ and T helper 17 cell‐related genes in human skin tissue as identified via transcriptome analysis

“…In addition, the Th17 cell-related chemokines are closely intimated with AhR and psoriasis. [40][41][42][43] The results obtained from human skin tissue were further confirmed in the human keratinocyte cell lines. PM2.5 treatment enhanced the expression of IL-6 and IL-36G.…”

“…[36][37][38][39] It has also been reported that environmental contaminants can exacerbate barrier dysfunction and exacerbate AD. 40 In our study discovered that PM2.5 acts as an AhR ligand to human skin tissue and expression levels of genes and protein of SPRR2A and KRT71 were increased.…”