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Transcriptomes of human monocytes and monocyte-derived macrophages with or without glucocorticoid treatment

ABSTRACT: Glucocorticoids (GCs) are essential steroid hormones that regulate the immune system. GCs have been widely used to treat various inflammation disorders and auto-immune diseases due to their potent immune suppressive properties.

ORGANISM(S): Homo sapiens

PROVIDER: GSE109439 | GEO | 2019/03/03

REPOSITORIES: GEO

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The epigenome and glucocorticoid receptor binding of human monocytes and monocyte-derived macrophages with or without glucocorticoid treatment

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Comparison of cellular and transcriptional responses to 1,25-dihydroxyvitamin D3 and glucocorticoids in peripheral blood mononuclear cells

Project description:Glucocorticoids (GC) and 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3) are steroid hormones with anti-inflammatory properties with enhanced effects when combined. We previously showed that transcriptional response to GCs was correlated with inter-individual and inter-ethnic cellular response. Here, we profiled cellular and transcriptional responses to 1,25(OH)2 D3 from the same donors. We studied cellular response to combined treatment with GCs and 1,25(OH)2 D3 in a subset of individuals least responsive to GCs. We found that combination treatment had significantly greater inhibition of proliferation than with either steroid hormone alone. Overlapping differentially expressed (DE) genes between the two hormones were enriched for adaptive and innate immune processes. Non-overlapping differentially expressed genes with 1,25(OH)2 D3 treatment were enriched for pathways involving the electron transport chain, while with GC treatment, non-overlapping genes were enriched for RNA-related processes. These results suggest that 1,25(OH)2 D3 enhances GC anti-inflammatory properties through a number of shared and non-shared transcriptionally-mediated pathways. Total RNA was obtained from aliquots of peripheral blood mononuclear cells treated with 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3) for 8 and 24 hours. These data were analyzed together with previously published data from expression analysis of PBMC aliquots collected in parallel to these and treated with dexamethasone or vehicle (EtOH).

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Comparison of cellular and transcriptional responses to 1,25-dihydroxyvitamin D3 and glucocorticoids in peripheral blood mononuclear cells

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Differential effect of glucocorticoids on the activation of monocytes and macrophages

Project description:The Glucocorticoid receptor (GR/NR3C1) is expressed in almost all immune cells. Glucocorticoids (GCs) are potent regulators of inflammation with effects mainly immunosuppressive. While, GCs have pleiotropic effects on Macrophages exhibiting complex properties with enhancing as well as suppressive effects on inflammatory processes depending on their stage of differentiation and activation, the mechanisms of GCs actions on Monocytes and Macrophages and their contribution to systemic anti-inflammatory effects remain unclear. Previously we have demonstrated that NLRP3 expression is induced by GCs in macrophages differentiated from monocytes-THP-1 but not in monocytes. These findings raise the possibility that the stage of myeloid differentiation and the cellular environment dictates the actions of GR from a pro- or anti-inflammatory perspective. Moreover, our preliminary results using the same cell line THP-1 show that the differentiation process from monocytes to macrophages also is related with the downregulation of GR induced by dex.

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Genetic mapping with multiple levels of phenotypic information reveals new determinants of lymphocyte glucocorticoid sensitivity

Project description:Clinical response to glucocorticoids (GCs), steroid hormones widely used as pharmaceuticals, varies extensively, with many patients (~30%) showing a weak response to treatment. Although little is known about the molecular basis of this variation, regulatory polymorphisms are likely to play a key role as GCs act largely through activation of a transcription factor, the GC receptor. In an effort to characterize the molecular basis of variation in GC sensitivity, we measured in vitro lymphocyte GC sensitivity (LGS) and transcriptome-wide response to GCs in peripheral blood mononuclear cells (PBMCs) from African-American healthy donors. We found that variation in LGS was correlated with transcriptional response at 27 genes (FDR<0.1). Furthermore, a genome-wide association scan revealed a quantitative trait locus (QTL) for LGS (rs11129354, P=4x10-8) that was also associated with transcriptional response at multiple genes, including many (14 of 27) where transcriptional response was correlated with LGS. Using allelic imbalance assays, we show that this QTL is a GC-dependent cis-regulatory polymorphism for RBMS3, which encodes an RNA-binding protein known as a tumor suppressor. We found that siRNA-mediated knockdown of RBMS3 expression increases cellular proliferation in PBMCs, consistent with the role of the gene as a negative regulator of proliferation. We propose that differences in LGS reflect variation in transcriptional response, which are influenced by a GC-dependent regulatory polymorphism that acts in cis relative to RBMS3 and in trans to affect the transcriptional response of multiple distant genes. Total RNA was obtained from paired aliquots of peripheral blood mononuclear cells treated with dexamethasone and phytohemagglutinin, vehicle (EtOH) and phytohemagglutinin, or blank (no treatment) for 6 hours.

2013-09-01 | E-GEOD-48801 | biostudies-arrayexpress

Differential effect of glucocorticoids on the activation of monocytes and macrophages.

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

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