Gene expression profiling of novel glucocorticoids for severe asthma in RAW264.7 cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE119789 | GEO | 2019/03/11
REPOSITORIES: GEO
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Project description:Gene expression profiling of novel glucocorticoids for severe asthma in RAW264.7 cells
| PRJNA490322 | ENA
Project description:To investigate the anti-inflammation activity of novel glucocorticoids on gene expression of macrohpage cells, we use mouse macrophage RAW264.7 cells to profiling gene expression pattern of novel glucocorticoids upon the onset of inflammation response.
2015-10-06 | GSE73733 | GEO
Project description:Glucocorticoids (GCs) are widely used as anti-inflammatory drugs, but their long-term use has severe metabolic side effects. Here, by treating multiple patient-derived adipose stem cell-derived adipocytes and iPSC-derived hepatocytes with the potent GC dexamethasone (Dex), we uncovered cell type-specific and individual-specific GC-dependent transcriptomes and glucocorticoid receptor (GR) cistromes. Patient-specific GR binding could be traced to single nucleotide polymorphisms (SNPs) that altered the binding motifs of GR or its cooperating factors. We also discovered another set of genetic variants that modulated Dex response through affecting chromatin accessibility or chromatin architecture. Several SNPs that altered Dex-regulated GR binding and gene expression controlled Dex-driven metabolic perturbations and, remarkably, predicted metabolic side-effects of GC-treated patients. These data validate a patient stem cell-based experimental framework to discover genetic variants that impact GR function and individual responses to GC drugs, with implications for developing personalized therapies.
2021-06-23 | GSE163061 | GEO
Project description:The glucocorticoid receptor (GR) is a crucial drug target in multiple myeloma as its activation with glucocorticoids effectively triggers myeloma cell death. However, as high-dose glucocorticoids are also associated with deleterious side effects, novel approaches are urgently needed to improve GR’s action in myeloma. Here we reveal a functional crosstalk between GR and the mineralocorticoid receptor (MR) that culminates in improved myeloma cell killing. We show that the GR agonist Dexamethasone (Dex) downregulates MR levels in a GR-dependent way in myeloma cells. Co-treatment of Dex with the MR antagonist Spironolactone (Spi) enhances Dex-induced cell killing in primary, newly diagnosed GC-sensitive myeloma cells, while in a relapsed GC-resistant setting, Spi alone induces distinct myeloma cell killing. On a mechanistic level, we find that a GR-MR crosstalk is arising from an endogenous interaction between GR and MR in myeloma cells. Quantitative dimerization assays show that Spi reduces Dex-induced GR-MR heterodimerization and completely abolishes Dex-induced MR MR homodimerization but leaves GR-GR homodimerization intact. Unbiased transcriptomics further reveals that c-myc and many of its target genes are downregulated most by Dex and Spi combined, while proteomics analyses identify that several metabolic hallmarks are modulated most by this combination treatment. Finally, we identified a subset of Dex+Spi downregulated genes and proteins that may predict prognosis in the CoMMpass patient cohort. Our study demonstrates that GR-MR crosstalk is therapeutically relevant in myeloma as it provides novel strategies towards glucocorticoid-based dose-reduction.
2023-10-24 | PXD043635 | Pride
Project description:Approximately 20-25% of patients with acute lymphoblastic leukemia (ALL) relapse after initial chemotherapy and become resistant to glucocorticoids (GC). Although GC signaling act on well-defined transcriptional responses via GC receptors (GCR), there is emerging evidence that GC also mediate transcription-independent signaling events that appear to be very rapid. We previously established that rapid calcium-mediated cell survival signals, triggered by GC stimulation, are involved in the resistance to GC anti-leukemic effects. Furthermore, we demonstrated that chelating intracellular calcium with Bapta-AM or inhibiting downstream ERK1/2 signaling with PD98059 overcame GC resistance in ALL samples. Here, we investigate the potential role of PLC in GC resistance. We identified that Dexamethasone (Dex) induced cytosolic calcium release via a mechanism involving the cell surface receptor of CXCL12 (CXCR4) internalization and subsequent activation of PLC signalosome. We found that PLC inhibition was able to induce cell death in GC-resistant B-ALL cells by compromising the expression of genes in several metabolic pathways including cell cycle checkpoints, glycolysis and mitochondrial function. These results establish a role for nongenomic signaling in ALL resistance to GC and support identifying novel therapeutics targeting Ca2+ signaling to restore GC sensitivity.
2024-04-01 | GSE214990 | GEO
Project description:Analysis of 3T3-L1 adipocytes treeated with dexamethasone (Dex) for 6 hours. Dex is a synthetic glucorticoid (GC) receptor agonist. Results provide insight into the effect of glucocorticoids on adipocytes.
2010-09-15 | GSE24105 | GEO
Project description:Mathematical modeling of immune modulation by glucocorticoids
Konstantin Yakimchuk
https://doi.org/10.1016/j.biosystems.2019.104066
Abstract
The cellular and molecular mechanisms of immunomodulatory actions of glucocorticoids (GC) remain to be identified. Using our experimental findings, a mathematical model based on a system of ordinary differential equations for characterization of the regulation of anti-tumor immune activity by the both direct and indirect GC effects was generated to study the effects of GC treatment on effector CD8+ T cells, GC-generated tolerogenic dendritic cells (DC), regulatory T cells and the growth of lymphoma cells. In addition, we compared the data from in vivo and in silico experiments. The mathematical simulations indicated that treatment with GCs may suppress anti-tumor immune response in a dose-dependent manner. The model simulations were in line with earlier experimental observations of inhibitory effects of GCs on T and NK cells and DCs. The results of this study might be useful for predicting clinical outcomes in patients receiving GC therapy.
2020-01-06 | MODEL1912170005 | BioModels
Project description:With the aim of finding small molecules that stimulate erythropoiesis earlier than erythropoietin and that enhance CFU-E production, we studied the mechanism by which glucocorticoids increase CFU-E formation. Using BFU-E and CFU-E progenitors purified by a new technique, we demonstrate that glucocorticoids stimulate the earliest (BFU-E) progenitors to undergo limited self-renewal, which increases formation of CFU-E cells > 20-fold. Interestingly, glucocorticoids induce expression of genes in BFU-E cells that contain promoter regions highly enriched for hypoxia-induced factor 1 alpha (HIF1a) binding sites. This suggests activation of HIF1a may enhance or replace the effect of glucocorticoids on BFU-E self-renewal. Indeed, HIF1a activation by a prolyl hydroxylase inhibitor (PHI) synergizes with glucocorticoids and enhances production of CFU-Es 170-fold. Since PHIs are able to increase erythroblast production at very low concentrations of glucocorticoids, PHI-induced stimulation of BFU-E progenitors thus represents a conceptually new therapeutic window for treating Epo-resistant anemia. RNA-Seq was performed on enriched populations of BFU-E, CFU-E and Ter119+ as well as BFU-E enriched cells treated with Dex and DMOG
2010-12-21 | E-GEOD-26086 | biostudies-arrayexpress
Project description:Nuclear interaction studies by ChIP coupled with mass spectrometry identified the COMPASS/SETD1A complex as interaction partner of the glucocorticoid receptor (GR) in murine bone marrow-derived macrophages (BMDMs). Here, we profiled H3K4me1, H3K4me2 and H3K4me3 in wild-type and Setd1a hypermorphic (Setd1aDel/+) Raw264.7 cells after LPS and Dex+LPS stimulation by spike-in ChIP-Seq.
2020-12-31 | GSE138017 | GEO
Project description:Glucocorticoids (GC) are the mainstay treatment option for acute and chronic inflammatory conditions including autoimmune and allergic diseases. Despite the broad usage of GC in managing inflammatory conditions, the mechanisms by which GC exerts its immune modulatory functions remain poorly understood. Here, utilizing murine autoimmune and allergic inflammation models we report that Foxp3+ regulatory T (Treg) cells are the primary target cells of GC necessary for its anti-inflammatory functions. Dexamethasone (Dex) administered in the absence of Tregs was unable to inhibit inflammatory responses, and adoptive Treg cell transfer restored the control. Glucocorticoid receptor (GR) expression in Treg cells was essential, suggesting a direct involvement of Treg cells. Genome-wide RNA sequencing analysis uncovered a unique Dex-induced gene signature in Treg cells. miRNA-342-3p was induced by Dex treatment only in inducible Treg cells, and mTORC2 protein, Rictor, expression was directly controlled by miRNA-342. Modulation of miRNA-342 expression level directly controlled Treg cell suppressive functions by altering metabolic profiles. Collectively, our results uncover for the first time a novel pathway by which GC interferes with inflammatory responses via miR-342-dependent metabolic control in Treg cells.
2020-08-07 | GSE136969 | GEO