Indirect co-cultivation of HepG2 with differentiated THP-1 cells induces AHR signalling and release of pro-inflammatory cytokines.
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ABSTRACT:
PROVIDER: PRJNA588420 | ENA |
REPOSITORIES: ENA
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Project description:HepG2 and THP-1 cells, the latter differentiated by phorbol 12-myristate 13-acetate (PMA), were co-cultured and characterized for typical liver-specific functions, such as xenobiotic detoxification, lipid and cholesterol metabolism. Furthermore, liver injury-associated pathways, such as inflammation, were studied. In general, the co-cultivation of these cells produced a pro-inflammatory system, as indicated by increased levels of cytokines (IL-8, TGF-α, IL-6, GM-CSF, G-CSF, TGF-β, and hFGF) in the respective supernatant. Increased expression levels of target genes of the aryl hydrocarbon receptor (AHR), e.g., CYP1A1, CYP1A2 and CYP1B1, were detected, accompanied by the increased enzyme activity of CYP1A1. Moreover, transcriptome analyses indicated a significant upregulation of cholesterol biosynthesis, which could be reduced to baseline levels by lovastatin. In contrast, total de novo lipid synthesis was reduced in co-cultured HepG2 cells. Key events of the adverse outcome pathway (AOP) for fibrosis were activated by the co-cultivation, however, no increase in the concentration of extracellular collagen was detected. This indicates, that AOP should be used with care. In summary, the indirect co-culture of HepG2/THP 1 cells results in an increased release of pro-inflammatory cytokines, an activation of the AHR pathway and an increased enzymatic CYP1A activity.
2020-08-06 | GSE140141 | GEO
Project description:Atopic dermatitis is increasing worldwide, correlating with air pollutions. Various organic components of pollutants activate transcription factor AhR (aryl-hydrocarbon receptor). We have established AhR-CA mice, whose keratinocytes express constitutive-active AhR, and these mice developed atopic dermatitis-like frequent scratching and allergic inflammation. In this study we performed ChIP-seq analyses and identified keratinocyte-specific AhR target genes, including inflammatory cytokines Tslp and IL33, and neurotrophic factor Artemin. While AhR-CA mice exhibited epidermal hyperinnervation and alloknesis leading to hypersensitivity to pruritus, blockade of Artemin alleviated these phenotypes. AhR-CA mice showed scratching-induced barrier insufficiency and enhanced sensitization to epicutaneously-applied antigens, recapitulating human atopic dermatitis. Consistently, AhR activation and Artemin expression was detected in the epidermis of atopic dermatitis patients and keratinocytes exposed to air pollutants. Thus, AhR in keratinocytes senses the environmental stimuli and responds to them through moderating inflammation. We propose a mechanism in which air pollution induces atopic dermatitis through AhR activation.
2016-11-13 | GSE72449 | GEO
Project description:Atopic dermatitis is increasing worldwide, correlating with air pollutions. Various organic components of pollutants activate transcription factor AhR (aryl-hydrocarbon receptor). We have established AhR-CA mice, whose keratinocytes express constitutive-active AhR, and these mice developed atopic dermatitis-like frequent scratching and allergic inflammation. In this study we performed ChIP-seq analyses and identified keratinocyte-specific AhR target genes, including inflammatory cytokines Tslp and IL33, and neurotrophic factor Artemin. While AhR-CA mice exhibited epidermal hyperinnervation and alloknesis leading to hypersensitivity to pruritus, blockade of Artemin alleviated these phenotypes. AhR-CA mice showed scratching-induced barrier insufficiency and enhanced sensitization to epicutaneously-applied antigens, recapitulating human atopic dermatitis. Consistently, AhR activation and Artemin expression was detected in the epidermis of atopic dermatitis patients and keratinocytes exposed to air pollutants. Thus, AhR in keratinocytes senses the environmental stimuli and responds to them through moderating inflammation. We propose a mechanism in which air pollution induces atopic dermatitis through AhR activation.
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Project description:The transcriptional program of early embryonic development is tightly regulated by a set of well-defined transcription factors that suppress premature expression of differentiation genes and sustain the pluripotent identity. It is generally accepted that this program can be perturbed by environmental factors such as chemical pollutants, however the precise molecular mechanisms remain unknown. The Aryl Hydrocarbon Receptor (AHR) is a widely expressed nuclear receptor that senses environmental stimuli and modulates target gene expression. Here, we show that ectopic activation of AHR during early differentiation disrupts the differentiation program via the chromatin remodeling complex NuRD. The activated AHR/NuRD complex altered the expression of differentiation-specific genes that control the first two developmental decisions without affecting the pluripotency program. These findings identify a novel mechanism that allows environmental stimuli to disrupt embryonic development through AHR signaling.
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Project description:The AhR is a ligand activated transcription factor that may be important in normal skin physiology. We compared gene expression profiles between AhR Wt and AhR KO primary mouse keratinocyte cultures. We identified 391 genes that were differentially expressed with a 1.5 fold cutoff and p<.05, and identified the AhR as an important regulator of genes involved in normal epidermal differentiation. AhR Wt primary keratinocyte cultures (n=4) were compared with AhR KO primary keratinocyte cultures (n=3)
2015-07-01 | E-GEOD-62490 | biostudies-arrayexpress
Project description:The Aryl Hydrocarbon Receptor (AHR) regulates the expression of numerous genes in response to activation by agonists including xenobiotics. Although it is well appreciated that environmental signals and cell intrinsic features may modulate this transcriptional response, how it is mechanistically achieved remains poorly understood. We show that Hexokinase 2 (HK2) a metabolic enzyme fuelling cancer cell growth, is a transcriptional target of AHR as well as a modulator of its activity. Expression of HK2 is positively regulated by AHR upon exposure to agonists both in human cells and in mice lung tissues. Conversely, over-expression of HK2 regulates the abundance of many proteins involved in the regulation of AHR signalling and these changes are linked with altered AHR expression levels and transcriptional activity. HK2 expression also shows a negative correlation with AHR promoter methylation in tumours, and these tumours with high HK2 expression and low AHR methylation are associated with a worse overall survival in patients. In sum, our study provides novel insights into how AHR signalling is regulated which may help our understanding of the context-specific effects of this pathway and may have implications in cancer.
2022-05-31 | PXD028992 | Pride
Project description:The AhR is a ligand activated transcription factor that may be important in normal skin physiology. We compared gene expression profiles between AhR Wt and AhR KO primary mouse keratinocyte cultures. We identified 391 genes that were differentially expressed with a 1.5 fold cutoff and p<.05, and identified the AhR as an important regulator of genes involved in normal epidermal differentiation.
2015-07-01 | GSE62490 | GEO
Project description:Emerging studies revealed an immunomodulatory role of the Aryl hydrocarbon receptor (AhR), a receptor sensing environmental contaminants, and involved in their detoxification. Besides its function as a transcription factor, AhR can participate in non-genomic signaling through ubiquitination and phosphorylation-dependent processes. In this study, a multi-PTM-omics approach, including proteome, ubiquitome, and phosphoproteome, was utilized to examine mechanisms of non-genomic AhR-signaling in endotoxin-activated monocyte-derived macrophages. This dataset entails proteome and phosphoproteome data.
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