Gold Compound Induces Immune Suppression via AHR-TGF-β1 Signaling
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE125146 | GEO | 2019/01/16
REPOSITORIES: GEO
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Project description:Gold Compound Induces Immune Suppression via AHR-TGF-β1 Signaling
| PRJNA515323 | ENA
Project description:The aryl hydrocarbon receptor (AHR) is a widely-expressed ligand-dependent transcription-factor that mediates cellular responses to dioxins and other planar aromatic hydrocarbons. Indeed, AHR-null mice are refractory to the physiological effects of dioxin-exposure. Although some mechanistic aspects of AHR activity are well understood, the tissue-specificity of AHR effects remains unclear, both during development and following administration of exogenous ligands. Previously we employed studied the transcriptional responses of wild-type and AHR-null C57BL/6J mice to dioxin-exposure. We found that essentially all hepatic effects of dioxin were mediated by the AHR, and that large numbers of genes were affected by dioxin exposure. Surprisingly, we also identified a large effect of AHR genotype, even in the absence of dioxin-exposure. To help assess the tissue-specificity of AHR activity we replicated that prior study in the kidney from the same animals previously studied, and extensively compared the hepatic and renal transcriptional profiles. We find that dioxin-exposure causes essentially no transcriptional effects in the absence of a functional AHR in either liver or kidney. Surprisingly, aside from a number of well-established AHR target genes, dioxin-exposure has few effects in animals harbouring a wild-type AHR. By contrast, AHR genotype profoundly remodels the renal transcriptome, and is associated with perturbation of specific functional pathways and with specific DNA motifs. Our results demonstrate the importance of inter-tissue comparisons and highlight the basal role of AHR activity in renal and hepatic development or normal physiology. Two-Factor, Two-Level. AHRnull and wildtype mice were treated with dioxin (TCDD) or corn oil vehicle. 3 replicates per treatment for AHRnull mice, 6 replicates of dioxin treatment for wildtype mice, and 5 replicates of corn oil treatment for wildtype mice.
2009-09-21 | E-GEOD-15858 | biostudies-arrayexpress
Project description:The aryl hydrocarbon receptor (AHR) is a widely-expressed ligand-dependent transcription-factor that mediates cellular responses to dioxins and other planar aromatic hydrocarbons. Indeed, AHR-null mice are refractory to the physiological effects of dioxin-exposure. Although some mechanistic aspects of AHR activity are well understood, the tissue-specificity of AHR effects remains unclear, both during development and following administration of exogenous ligands. Previously we employed studied the transcriptional responses of wild-type and AHR-null C57BL/6J mice to dioxin-exposure. We found that essentially all hepatic effects of dioxin were mediated by the AHR, and that large numbers of genes were affected by dioxin exposure. Surprisingly, we also identified a large effect of AHR genotype, even in the absence of dioxin-exposure. To help assess the tissue-specificity of AHR activity we replicated that prior study in the kidney from the same animals previously studied, and extensively compared the hepatic and renal transcriptional profiles. We find that dioxin-exposure causes essentially no transcriptional effects in the absence of a functional AHR in either liver or kidney. Surprisingly, aside from a number of well-established AHR target genes, dioxin-exposure has few effects in animals harbouring a wild-type AHR. By contrast, AHR genotype profoundly remodels the renal transcriptome, and is associated with perturbation of specific functional pathways and with specific DNA motifs. Our results demonstrate the importance of inter-tissue comparisons and highlight the basal role of AHR activity in renal and hepatic development or normal physiology. Two-Factor, Two-Level. AHRnull and wildtype mice were treated with dioxin (TCDD) or corn oil vehicle. 3 replicates per treatment for AHRnull mice, and 6 replicates per treatment for wildtype mice.
2009-09-21 | E-GEOD-15857 | biostudies-arrayexpress
Project description:The aryl hydrocarbon receptor (AHR) is a widely-expressed ligand-dependent transcription-factor that mediates cellular responses to dioxins and other planar aromatic hydrocarbons. Indeed, AHR-null mice are refractory to the physiological effects of dioxin-exposure. Although some mechanistic aspects of AHR activity are well understood, the tissue-specificity of AHR effects remains unclear, both during development and following administration of exogenous ligands. Previously we employed studied the transcriptional responses of wild-type and AHR-null C57BL/6J mice to dioxin-exposure. We found that essentially all hepatic effects of dioxin were mediated by the AHR, and that large numbers of genes were affected by dioxin exposure. Surprisingly, we also identified a large effect of AHR genotype, even in the absence of dioxin-exposure. To help assess the tissue-specificity of AHR activity we replicated that prior study in the kidney from the same animals previously studied, and extensively compared the hepatic and renal transcriptional profiles. We find that dioxin-exposure causes essentially no transcriptional effects in the absence of a functional AHR in either liver or kidney. Surprisingly, aside from a number of well-established AHR target genes, dioxin-exposure has few effects in animals harbouring a wild-type AHR. By contrast, AHR genotype profoundly remodels the renal transcriptome, and is associated with perturbation of specific functional pathways and with specific DNA motifs. Our results demonstrate the importance of inter-tissue comparisons and highlight the basal role of AHR activity in renal and hepatic development or normal physiology.
2009-09-21 | GSE15858 | GEO
Project description:The aryl hydrocarbon receptor (AHR) is a widely-expressed ligand-dependent transcription-factor that mediates cellular responses to dioxins and other planar aromatic hydrocarbons. Indeed, AHR-null mice are refractory to the physiological effects of dioxin-exposure. Although some mechanistic aspects of AHR activity are well understood, the tissue-specificity of AHR effects remains unclear, both during development and following administration of exogenous ligands. Previously we employed studied the transcriptional responses of wild-type and AHR-null C57BL/6J mice to dioxin-exposure. We found that essentially all hepatic effects of dioxin were mediated by the AHR, and that large numbers of genes were affected by dioxin exposure. Surprisingly, we also identified a large effect of AHR genotype, even in the absence of dioxin-exposure. To help assess the tissue-specificity of AHR activity we replicated that prior study in the kidney from the same animals previously studied, and extensively compared the hepatic and renal transcriptional profiles. We find that dioxin-exposure causes essentially no transcriptional effects in the absence of a functional AHR in either liver or kidney. Surprisingly, aside from a number of well-established AHR target genes, dioxin-exposure has few effects in animals harbouring a wild-type AHR. By contrast, AHR genotype profoundly remodels the renal transcriptome, and is associated with perturbation of specific functional pathways and with specific DNA motifs. Our results demonstrate the importance of inter-tissue comparisons and highlight the basal role of AHR activity in renal and hepatic development or normal physiology.
2009-09-21 | GSE15857 | GEO
Project description:Background: The Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is activated by xenobiotic chemicals that function as AHR ligands. The response to xenobiotic AHR ligands is toxicity and the induction of drug metabolizing enzymes. The impact of AHR knockdown on gene expression and pathways in human breast cancer cells in absence of xenobiotic AHR ligands has not been investigated on a genome-wide scale. Methods: MCF-7 cells were used as a model of human breast cancer. The AHR was silenced with short interfering RNA against AHR (siAHR). RNA-sequencing coupled with Ingenuity pathway analysis (IPA) was used to determine the impact of AHR knockdown on gene expression and pathways in the absence of xenobiotic AHR ligands. Western blot analysis and recombinant tumor necrosis factor (TNF) was used to investigate the impact of AHR knockdown on TNF induction of MNSOD expression. Results: We found that the AHR is transcriptionally active in MCF-7 breast cancer cells in the absence of xenobiotic AHR ligands. In total, the expression of 634 genes was significantly changed in AHR knockdown cells compared to controls at a false discovery rate of < 10%. The analysis confirmed that drug metabolizing enzymes were AHR targets; however, we found that AHR also promoted the expression of genes that were not directly related to the metabolism of xenobiotics, such as those involved in lipid and eicosanoid synthesis. Gene pathway analysis of the AHR regulated gene dataset predicted TNF activity to be reduced in AHR knockdown cells. Our finding that AHR knockdown inhibited TNF-stimulated increases in MNSOD expression confirmed this IPA prediction. Conclusions: This is the first gene expression profiling study of AHR knockdown breast cancer cells. Several known and novel AHR targets were identified. The results suggest that endogenous AHR regulation impacts eicosanoid synthesis by regulating gene expression. The IPA prediction of reduced TNF activity in AHR knockdown cells was confirmed by showing that TNF-induced increases in MNSOD expression was inhibited in AHR knockdown cells. The requirement of AHR for MNSOD activation is novel and provides a new link by which AHR may impact reactive oxidative species (ROS) signaling. Expression profiles by mRNA sequencing were generated for human MCF-7 cells transfected with cRNAi (6 replicates) or AHR-siRNA (5 replicates) for 36hr. Sequencing was performed on an Illumina HiSeq 1000 using a 2x100 base paired-end strategy.
2014-06-20 | E-GEOD-52036 | biostudies-arrayexpress
Project description:Background: The Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is activated by xenobiotic chemicals that function as AHR ligands. The response to xenobiotic AHR ligands is toxicity and the induction of drug metabolizing enzymes. The impact of AHR knockdown on gene expression and pathways in human breast cancer cells in absence of xenobiotic AHR ligands has not been investigated on a genome-wide scale. Methods: MCF-7 cells were used as a model of human breast cancer. The AHR was silenced with short interfering RNA against AHR (siAHR). RNA-sequencing coupled with Ingenuity pathway analysis (IPA) was used to determine the impact of AHR knockdown on gene expression and pathways in the absence of xenobiotic AHR ligands. Western blot analysis and recombinant tumor necrosis factor (TNF) was used to investigate the impact of AHR knockdown on TNF induction of MNSOD expression. Results: We found that the AHR is transcriptionally active in MCF-7 breast cancer cells in the absence of xenobiotic AHR ligands. In total, the expression of 634 genes was significantly changed in AHR knockdown cells compared to controls at a false discovery rate of < 10%. The analysis confirmed that drug metabolizing enzymes were AHR targets; however, we found that AHR also promoted the expression of genes that were not directly related to the metabolism of xenobiotics, such as those involved in lipid and eicosanoid synthesis. Gene pathway analysis of the AHR regulated gene dataset predicted TNF activity to be reduced in AHR knockdown cells. Our finding that AHR knockdown inhibited TNF-stimulated increases in MNSOD expression confirmed this IPA prediction. Conclusions: This is the first gene expression profiling study of AHR knockdown breast cancer cells. Several known and novel AHR targets were identified. The results suggest that endogenous AHR regulation impacts eicosanoid synthesis by regulating gene expression. The IPA prediction of reduced TNF activity in AHR knockdown cells was confirmed by showing that TNF-induced increases in MNSOD expression was inhibited in AHR knockdown cells. The requirement of AHR for MNSOD activation is novel and provides a new link by which AHR may impact reactive oxidative species (ROS) signaling.
2014-06-20 | GSE52036 | GEO
Project description:The antimicrobial properties of silver have been exploited for many centuries and continue to gain interest in the fight against antimicrobial drug resistance. The broad-spectrum activity and low toxicity of silver has led to its incorporation into a wide range of novel antimicrobial agents, including N-heterocyclic carbene (NHC) complexes. These versatile organic compounds readily bind transition metals and allow various substitutions, ring sizes and general properties. The antimicrobial activity and in vivo efficacy of the NHC silver(I) acetate complex SBC3, derived from 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*), has previously been demonstrated, although the mode(s) of action of SBC3 remained unclear. Label-free quantitative (LFQ) proteomics was employed to analyse protein abundance changes in the yeast Candida parapsilosis in response to SBC3 treatment and gain insight into potential SBC3 targets. Proteomic analysis of C. parapsilosis following exposure to SBC3 revealed increased abundance in proteins associated with cell wall synthesis, detoxification and drug efflux that are indicative of a cell stress response. Significant decreases in proteins required for protein synthesis, amino acid biosynthesis and respiration offer potential insight into the growth-inhibitory mechanisms of SBC3. Exposure of C. parapsilosis to SBC3 lead to reduced adherence to epithelial cells and biofilm formation which may indicate the compound can reduce fungal virulence.
2022-06-28 | PXD025693 | Pride
Project description:The aryl hydrocarbon receptor (AhR) is a highly conserved ligand-dependent transcription factor that senses environmental toxins and endogenous ligands, thereby inducing detoxifying enzymes and modulating immune cell differentiation and responses. We hypothesized that AhR not only evolved to sense pollutants from the environment, but also insults of microbial origin. We demonstrate that bacterial pigmented virulence factors, namely the phenazines pyocyanin and 1-hydroxyphenazine from Pseudomonas aeruginosa and the naphthoquinone phthiocol from Mycobacterium tuberculosis, are ligands of AhR. AhR activation leads to degradation of these virulence factors and regulated cytokine and chemokine production. The relevance of AhR to host defense is underlined by heightened susceptibility of AhR-deficient mice, both to P. aeruginosa and M. tuberculosis. Our data demonstrate that AhR senses distinct bacterial virulence factors and controls anti-bacterial responses. We provide evidence for a previously unidentified role for AhR as an intracellular pattern recognition receptor, and identify bacterial pigmented virulence factors as a new class of pathogen-associated molecular patterns. Microarray experiments were performed as single-color hybridizations. Quality control and quantification of total RNA amount was assessed using an Agilent 2100 Bioanalyzer (Agilent Technologies) and a NanoDrop 1000 spectrophotometer (Kisker).
2014-01-01 | E-GEOD-48130 | biostudies-arrayexpress
Project description:Comparison of expression profiles detected in A549 cells exposed to DMSO, TCDD, and BaP for 2w Exposure to persistent ligands of aryl hydrocarbon receptor (AhR) has been found to cause lung cancer in experimental animals and lung adenocarcinomas are often associated with enhanced AhR expression and aberrant AhR activation. In order to better understand the action of toxic AhR ligands in lung epithelial cells, we performed global gene expression profiling in order to analyse TCDD- induced changes in A549 transcriptome, and compare them with changes in transcriptome of A549 cells exposed to BaP for 2w.
2019-09-01 | GSE122733 | GEO