Abstract
The aryl hydrocarbon receptor (AHR) is known to mediate the cellular reaction involved in processing environmental contaminants and, ultimately, preventing accumulation of unfavorable extra lipids and proteins. Glucocorticoid receptor (GR) mediates the expression of genes associated with anti-inflammatory properties. Because AHR and GR are closely related in lipid metabolic dysregulation and inflammation, we speculate that AHR and GR may play a crucial role in AMD pathogenesis and focus on their crosstalk in human retinal pigment epithelial cells (ARPE-19). However, how AHR and GR regulate each other's signaling pathways is still poorly understood. In this research, we demonstrate that GR attenuates AHR-mediated gene expression by inhibition of nuclear translocation of AHR mediated by TCDD. Chromatin immunoprecipitation analysis demonstrated that GR repress AHR recruitment and chromatin accessibility response to TCDD + Dex treatment leading to repression of AHR target genes. In contrast, AHR facilitates GR-mediated expression in ARPE-19. AHR increases GR recruitment on GRE of GR target genes. Coimmunoprecipitation assay revealed that AHR is associated with GR in ARPE-19 cells and the interaction is enhanced by the addition of TCDD and Dex. Taken together, these studies provide a molecular mechanism of crosstalk between AHR and GR in target gene expression in ARPE-19 cells.
Highlights
Age-related macular degeneration (AMD) is characterized by degeneration of the retina
Previous studies have shown that aryl hydrocarbon receptor (AHR)- and GRmediated transcription is active in ARPE-19 cells with different target-gene specificity [26, 27], but there is no apparent study for their crosstalk in transcription process in ARPE19
To determine whether AHR affects Glucocorticoid receptor (GR)-mediated transcription or vice versa, ARPE-19 cells were cultured in DMEM/F-12 media, they were treated with TCDD and Dex alone or in combination, and mRNA expression of AHR target genes (CYP1A1, CYP1A2, and AHRR) (Figure 1(a)) and GR target genes (ANGPTL4, FKBP5, and GILZ) (Figure 1(b)) were analyzed by quantitative real-time PCR
Summary
Age-related macular degeneration (AMD) is characterized by degeneration of the retina. Physiological changes of AMD begin with an accumulation of extracellular deposit consisting of rich lipid and protein under the retinal pigment epithelial (RPE) layer and/or within Bruch’s membrane [2]. These deposits mainly regarded as drusen lead to RPE dysfunction, apoptosis, and eventually degeneration [3, 4]. Dry AMD takes up to 90% of the entire AMD patients [6]. It often shows RPE dysfunction and local hyperpigmentation or bleaching [5]. The molecular understanding of RPE dysfunction and mechanism for extracellular deposit accumulation is still unknown
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