Differential effect of glucocorticoids on the activation of monocytes and macrophages
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE135130 | GEO | 2020/01/27
REPOSITORIES: GEO
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Project description:Glucocorticoids (GCs) reduce the expression of many genes induced in inflammatory conditions in vivo or by pro-inflammatory stimuli in vitro acting on the Glucocorticoid receptor (GR/NR3C1). However, GCs have pleiotropic effects on the immune system. Monocytes and macrophages are important cells of the innate immune system, exhibiting complex properties with enhancing as well as suppressive effects on inflammatory processes depending on their stage of activation and differentiation. Macrophages contribute to host defense, tissue remodeling and wound healing The mechanisms of GCs actions on monocytes and macrophages and their contribution to systemic anti-inflammatory effects remain unclear. These effects on activation GCs in monocytes and macrophages were investigated using the human monocytic cell line THP-1 and differentiation protocol PMA. Monocytes-THP1 and macrophages derived-monocytes were exposed for 6 hours to 100 nM of dexamethasone (Dex) and analyzed by microarrays. In macrophages-derived monocytes with respect to monocytes-THP-1, the number of genes differentially regulated was almost twice, among these, genes related with pro-inflammatory pathways, like TNFa, CXCL1 and GZMA. Interestingly, one of the genes differentially regulated (decreased) in macrophages exposed to Dex was the GR itself. If this effect modifies the inflammatory function of macrophages derived-monocyte is a question that will be evaluated through this study.
2020-01-27 | GSE135165 | GEO
Project description:Environmental cues during gestation could exert transgenerational effects on behavior mainly through changes in epigenetic marks such as DNA methylation. However, the role of histone modifications in the inheritance of acquired phenotypes remains largely unknown in mammals. Here, we report that gestational choline supplementation (GCS) in maternal mice exerts anxiolytic effects on male offspring across 2 generations. Correspondingly, GCS-induced H3K9 hyperacetylation in the Nr3c1 promoter in male hippocampus leads to upregulation of Nr3c1 and its encoded protein, glucocorticoid receptor (GR), across 2 generations through the male germline. Furthermore, inhibition of CREB-binding protein (CBP) histone acetyltransferase (HAT) function restored GCS-induced epigenetic and behavioral alterations, suggesting that CBP function as a HAT to increase Nr3c1 expression through H3K9 hyperacetylation. Thus, GCS-induced GR upregulation through CBP-mediated H3K9 hyperacetylation in the Nr3c1 promoter is associated with anxiolytic behavior in male offspring, highlighting the role of histone modification in acquired phenotypes across mammalian generations.
2021-09-01 | GSE84316 | GEO
Project description:Environmental cues during gestation could exert transgenerational effects on behavior mainly through changes in epigenetic marks such as DNA methylation. However, the role of histone modifications in the inheritance of acquired phenotypes remains largely unknown in mammals. Here, we report that gestational choline supplementation (GCS) in maternal mice exerts anxiolytic effects on male offspring across 2 generations. Correspondingly, GCS-induced H3K9 hyperacetylation in the Nr3c1 promoter in male hippocampus leads to upregulation of Nr3c1 and its encoded protein, glucocorticoid receptor (GR), across 2 generations through the male germline. Furthermore, inhibition of CREB-binding protein (CBP) histone acetyltransferase (HAT) function restored GCS-induced epigenetic and behavioral alterations, suggesting that CBP function as a HAT to increase Nr3c1 expression through H3K9 hyperacetylation. Thus, GCS-induced GR upregulation through CBP-mediated H3K9 hyperacetylation in the Nr3c1 promoter is associated with anxiolytic behavior in male offspring, highlighting the role of histone modification in acquired phenotypes across mammalian generations.
2021-09-01 | GSE84315 | GEO
Project description:Environmental cues during gestation could exert transgenerational effects on behavior mainly through changes in epigenetic marks such as DNA methylation. However, the role of histone modifications in the inheritance of acquired phenotypes remains largely unknown in mammals. Here, we report that gestational choline supplementation (GCS) in maternal mice exerts anxiolytic effects on male offspring across 2 generations. Correspondingly, GCS-induced H3K9 hyperacetylation in the Nr3c1 promoter in male hippocampus leads to upregulation of Nr3c1 and its encoded protein, glucocorticoid receptor (GR), across 2 generations through the male germline. Furthermore, inhibition of CREB-binding protein (CBP) histone acetyltransferase (HAT) function restored GCS-induced epigenetic and behavioral alterations, suggesting that CBP function as a HAT to increase Nr3c1 expression through H3K9 hyperacetylation. Thus, GCS-induced GR upregulation through CBP-mediated H3K9 hyperacetylation in the Nr3c1 promoter is associated with anxiolytic behavior in male offspring, highlighting the role of histone modification in acquired phenotypes across mammalian generations.
2021-09-01 | GSE84314 | GEO
Project description:The functions of human testicular peritubular cells (HTPCs), which form a small compartment located between the seminiferous epithelium and the interstitials areas of the testis, go beyond intratesticular sperm transport and include immunological roles. The expression of the glucocorticoid receptor (GR/NR3C1) by these cells indicates that they are a target of glucocorticoids (GCs), yet detailed insights into consequences of GC actions are unknown. To address this point, we studied cultured HTPCs, which serve as a window into the human testis. We used a cytokine profiler assay to screen for changes in secreted cytokines upon dexamethasone (Dex) treatment and employed qPCR and ELISA studies to verify the results. Dex, used in a therapeutic concentration, decreased proinflammatory factors, including IL6, IL8, MCP1 and CXCL1 within 24 - 48 h. An siRNA-mediated knockdown of GR reduced these actions. Exposure to Dex resulted in reduced GR levels, implying that exposure to Dex could also reduce anti-inflammatory actions of Dex. To evaluate the influence of Dex on HTPCs further, we performed a proteomic analysis of cellular components and secreted proteins. Strong responses were detectable after 24 h (31 significantly altered cellular proteins) and more pronounced ones after 72 h (30 less abundant and 42 more abundant cellular proteins). Dex also altered the composition of the secretome (33 proteins decreased, 13 increased) after 72 h. Among the regulated proteins were ECM- and basement membrane components (e.g. FBLN2, COL1A2, COL3A1), as well as PTX3 and StAR. These results reveal that Dex via GR exerts profound actions in HTPCs. If transferrable to the human testis, changes specifically in ECM and the immunological state of the testis may result in men upon treatment with Dex for medical reasons. -Proteome Data Subset 72 h-
2023-03-11 | PXD033534 | Pride
Project description:The functions of human testicular peritubular cells (HTPCs), which form a small compartment located between the seminiferous epithelium and the interstitials areas of the testis, go beyond intratesticular sperm transport and include immunological roles. The expression of the glucocorticoid receptor (GR/NR3C1) by these cells indicates that they are a target of glucocorticoids (GCs), yet detailed insights into consequences of GC actions are unknown. To address this point, we studied cultured HTPCs, which serve as a window into the human testis. We used a cytokine profiler assay to screen for changes in secreted cytokines upon dexamethasone (Dex) treatment and employed qPCR and ELISA studies to verify the results. Dex, used in a therapeutic concentration, decreased proinflammatory factors, including IL6, IL8, MCP1 and CXCL1 within 24 - 48 h. An siRNA-mediated knockdown of GR reduced these actions. Exposure to Dex resulted in reduced GR levels, implying that exposure to Dex could also reduce anti-inflammatory actions of Dex. To evaluate the influence of Dex on HTPCs further, we performed a proteomic analysis of cellular components and secreted proteins. Strong responses were detectable after 24 h (31 significantly altered cellular proteins) and more pronounced ones after 72 h (30 less abundant and 42 more abundant cellular proteins). Dex also altered the composition of the secretome (33 proteins decreased, 13 increased) after 72 h. Among the regulated proteins were ECM- and basement membrane components (e.g. FBLN2, COL1A2, COL3A1), as well as PTX3 and StAR. These results reveal that Dex via GR exerts profound actions in HTPCs. If transferrable to the human testis, changes specifically in ECM and the immunological state of the testis may result in men upon treatment with Dex for medical reasons. -Proteome Data Subset 24 h-
2023-03-11 | PXD033514 | Pride
Project description:The functions of human testicular peritubular cells (HTPCs), which form a small compartment located between the seminiferous epithelium and the interstitials areas of the testis, go beyond intratesticular sperm transport and include immunological roles. The expression of the glucocorticoid receptor (GR/NR3C1) by these cells indicates that they are a target of glucocorticoids (GCs), yet detailed insights into consequences of GC actions are unknown. To address this point, we studied cultured HTPCs, which serve as a window into the human testis. We used a cytokine profiler assay to screen for changes in secreted cytokines upon dexamethasone (Dex) treatment and employed qPCR and ELISA studies to verify the results. Dex, used in a therapeutic concentration, decreased proinflammatory factors, including IL6, IL8, MCP1 and CXCL1 within 24 - 48 h. An siRNA-mediated knockdown of GR reduced these actions. Exposure to Dex resulted in reduced GR levels, implying that exposure to Dex could also reduce anti-inflammatory actions of Dex. To evaluate the influence of Dex on HTPCs further, we performed a proteomic analysis of cellular components and secreted proteins. Strong responses were detectable after 24 h (31 significantly altered cellular proteins) and more pronounced ones after 72 h (30 less abundant and 42 more abundant cellular proteins). Dex also altered the composition of the secretome (33 proteins decreased, 13 increased) after 72 h. Among the regulated proteins were ECM- and basement membrane components (e.g. FBLN2, COL1A2, COL3A1), as well as PTX3 and StAR. These results reveal that Dex via GR exerts profound actions in HTPCs. If transferrable to the human testis, changes specifically in ECM and the immunological state of the testis may result in men upon treatment with Dex for medical reasons. -Secretome Data Subset-
2023-03-11 | PXD033504 | Pride
Project description:Glucocorticoids (GCs) are important hormones involved in the regulation of multiple physiologic functions. GCs are also widely used in anti-inflammatory/immunosuppressant drugs. GCs are synthesized by the adrenal cortex as part of the hypothalamus-pituitary-adrenal axis and also by intestinal epithelial cells, among other peripheral sites. GCs are one of the main therapy choices for the exacerbations of inflammatory bowel disease, but they are not useful to prolong remission, and development of tolerance with secondary treatment failure is frequent. Thus, GC actions at the intestinal epithelial level are of great importance, both physiologically and pharmacologically. We generated a tamoxifen-inducible nuclear receptor subfamily 3 group C member 1 (NR3C1)ΔIEC mouse model to study the effects of GCs on epithelial cells in vivo. Nr3c1 deletion in epithelial cells of the small intestine and colon was associated with limited colonic inflammation at 1 wk postdeletion, involving augmented epithelial proliferation and mucus production, plus local and systemic immune/inflammatory changes. This phenotype regressed substantially, but not completely, after 2 wk. The mechanism may involve augmented inflammatory signaling by epithelial cells or defective barrier function. We conclude that the epithelial GC receptor plays a significant role in colonic homeostasis in basal conditions, but its deficiency can be compensated in the short term. Future studies are required to assess the impact of Nr3c1 deletion in other conditions such as experimental colitis.-Aranda, C. J., Arredondo-Amador, M., Ocón, B., Lavín, J. L., Aransay, A. M., Martínez-Augustin, O., Sánchez de Medina, F. Intestinal epithelial deletion of the glucocorticoid receptor NR3C1 alters expression of inflammatory mediators and barrier function.
2019-11-05 | GSE126366 | GEO
Project description:Despite the widespread use of glucocorticoids (GCs) for treating inflammatory conditions, the underlying mechanisms of their anti-inflammatory effects are not understood. Moreover, the majority of molecular investigations have examined the effects of glucocorticoid receptor (GR) activation prior to inflammatory challenges. However, clinically relevant situations are emulated by a GC intervention initiated in the midst of rampant inflammatory responses. To characterize the effects of a late GC treatment, we performed systematic profiling of macrophage transcriptional and regulatory landscapes with Dexamethasone (Dex) treatment either before or after stimulation by lipopolysaccharide (LPS). GR activation by Dex following LPS stimulation had a similar anti-inflammatory profile in comparison to GR pre-activation, while ameliorating the disruption of metabolic genes. Unexpectedly, the chromatin occupancy pattern of GR is not predictive of the Dex-regulated expression changes and shows little evidence for the widely accepted ‘trans-repression by tethering’ model. Rather, we find that GR activation results in global blockade of NF-κB binding to chromatin. Integrative analyses of gene expression, transcription factor occupancy, and chromatin accessibility data highlight distinct mechanisms through which GR controls inflammatory macrophages: prevention of NF-κB chromatin occupancy and activation of negative regulators such as Nfkbia, Dusp1, Tnfaip3, and Tsc22d3. Our investigation with differentially timed GC treatments reveals molecular mechanisms underlying therapeutic actions of GR for modulating the ‘inflamed epigenome’.
2017-08-08 | GSE93738 | GEO
Project description:Despite the widespread use of glucocorticoids (GCs) for treating inflammatory conditions, the underlying mechanisms of their anti-inflammatory effects are not understood. Moreover, the majority of molecular investigations have examined the effects of glucocorticoid receptor (GR) activation prior to inflammatory challenges. However, clinically relevant situations are emulated by a GC intervention initiated in the midst of rampant inflammatory responses. To characterize the effects of a late GC treatment, we performed systematic profiling of macrophage transcriptional and regulatory landscapes with Dexamethasone (Dex) treatment either before or after stimulation by lipopolysaccharide (LPS). GR activation by Dex following LPS stimulation had a similar anti-inflammatory profile in comparison to GR pre-activation, while ameliorating the disruption of metabolic genes. Unexpectedly, the chromatin occupancy pattern of GR is not predictive of the Dex-regulated expression changes and shows little evidence for the widely accepted ‘trans-repression by tethering’ model. Rather, we find that GR activation results in global blockade of NF-κB binding to chromatin. Integrative analyses of gene expression, transcription factor occupancy, and chromatin accessibility data highlight distinct mechanisms through which GR controls inflammatory macrophages: prevention of NF-κB chromatin occupancy and activation of negative regulators such as Nfkbia, Dusp1, Tnfaip3, and Tsc22d3. Our investigation with differentially timed GC treatments reveals molecular mechanisms underlying therapeutic actions of GR for modulating the ‘inflamed epigenome’.
2017-08-08 | GSE93736 | GEO