Glucocorticoid receptor dimers control intestinal STAT1-mediated IFN- and TNF-induced inflammation in mice
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ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PXD008608
PROVIDER: PRJNA453622 | ENA |
REPOSITORIES: ENA
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Project description:Tumor Necrosis Factor (TNF) is an important mediator in numerous inflammatory diseases, e.g. in inflammatory bowel diseases (IBD). In IBD, acute increases in TNF production can lead to disease flares. Glucocorticoids (GCs), which are steroids that bind and activate the glucocorticoid receptor (GR), are able to protect animals and humans against acute TNF-induced inflammatory symptoms. Mice with a poor transcriptional response of GR-dimer-dependent target genes were studied in a model of TNF-induced lethal inflammation. In contrast to the GRwt/wt mice, these GRdim/dim mice displayed a significant increase in TNF sensitivity and a lack of protection by the GC dexamethasone (DEX). Unchallenged GRdim/dim mice had a strong interferon-stimulated gene (ISG) signature, along with STAT1 upregulation and phosphorylation. This ISG signature was gut specific and, based on our studies with antibiotics, depended on the gut microbiota. GR dimers directly bound to short DNA sequences in the STAT1 promoter known as inverted repeat negative GRE (IR-nGRE) elements. Poor control of STAT1 in GRdim/dim mice led to failure to repress ISG genes resulting in excessive necroptosis induction by TNF. Our findings support a critical interplay between gut microbiota, interferons, necroptosis and GR in both the basal response to acute inflammatory challenges and in the pharmacological intervention by GCs.
2018-04-26 | GSE113691 | GEO
Project description:The use of glucocorticoids (GCs), which bind and activate the glucocorticoid receptor (GR), in systemic inflammatory response syndromes (SIRS) is disputed. Mice with a poor transcriptional response of dimer-dependent GR target genes were studied in a model of TNF-induced SIRS. These GR dim/dim mice display a significant increase in TNF sensitivity and a lack of protection by the GC dexamethasone (DEX). Unchallenged GR dim/dim mice have a strong interferon-stimulated gene (ISG) signature at the transcriptional level and this ISG signature is gut specific. Here, we used shotgun proteomics to study the regulation of ISG proteins in the ileum of GR dim/dim mice. Our data showed that unchallenged GR dim/dim mice have a strong interferon-stimulated gene (ISG) signature, along with STAT1 upregulation. Taken together, we show that GR dim/dim mice poorly control ISG expression resulting in excessive necroptosis induction by TNF. Our findings support a critical interplay between gut microbiota, interferons, necroptosis and GR in both the basal response to acute inflammatory challenges and in the pharmacological intervention by GCs.
2019-04-01 | PXD008608 | Pride
Project description:G-protein coupled receptors (GPCRs) have diverse roles in physiological processes, including immunity. Gs-coupled GPCRs increase while Gi-coupled ones decrease intracellular cAMP. Previous studies suggest that, in epithelial cells, Gs-coupled GPCRs enhance whereas Gi-coupled GPCRs suppress pro-inflammatory immune responses. In order to examine the issue, we chose beta2 adrenergic receptor and GPR40 as representatives of Gs- and Gi- coupled GPCRs, respectively, and examined their effects on TNF-alpha and IFN-gamma-(TNF-alpha + IFN-gamma) induced gene expression by HaCaT. We used microarrays to detail the global changes of gene expression induced by a beta2 adrenergic receptor agonist terbutaline or GPR40 agonist GW9508 pre-treatment in TNF-alpha + IFN-gamma - stimulated HaCaT cells. HaCaT cells were pre-treated with terbutaline or GW9508, TNF-alpha + IFN-gamma were then added, and cultured for another 24 h. Cells were then used for RNA extraction and hybridization on Affymetrix microarrays. We sought to clarify changes in gene expression after 1) TNF-alpha + IFN-gamma, 2) TNF-alpha + IFN-gamma + terbutaline, and 3) TNF-alpha + IFN-gamma + GW9508 treatment. To this end, we set 4 groups of samples; 1) unstimulated group, 2) TNF-alpha + IFN-gamma-stimulated group, 3) TNF-alpha + IFN-gamma + terbutaline-stimulated group, and 4) TNF-alpha + IFN-gamma + GW9508-stimulated group. In each group, HaCaT cells were stimulated in triplicate wells (n=3).
2010-12-01 | E-GEOD-20297 | biostudies-arrayexpress
Project description:A single high dose of IFN? activates powerful cellular responses in which many antiviral, pro-apoptotic, and anti-proliferative proteins are highly expressed. Since some of these proteins are deleterious, cells down-regulate this initial response rapidly. However, the expression of many antiviral proteins that do no harm is sustained, prolonging a substantial part of the initial antiviral response for days and also providing resistance to DNA damage. While the transcription factor ISGF3 (IRF9 and tyrosine-phosphorylated STATs 1 and 2) drives the first rapid response phase, the related factor un-phosphorylated ISGF3 (U-ISGF3), formed by IFN?-induced high levels of IRF9 and STATs 1 and 2 without tyrosine phosphorylation, drives the second prolonged response. The U-ISGF3-induced antiviral genes that show prolonged expression are driven by distinct interferon stimulated response elements (ISREs). Continuous exposure of cells to a low level of IFN?, often seen in cancers, leads to steady-state increased expression of only the U-ISGF3-dependent proteins, with no sustained increase of other IFN?-induced proteins, and to constitutive resistance to DNA damage. We classified genes into U-ISGF3-induced genes and classical ISGF3-induced genes using microarray data. We identified 150 genes that are up-regulated by IFN? after 6 h. Among these IFN?-induced genes, only 29 (20%) were induced by the up-regulation of Y701F-STAT1, indicating that these are induced by U-ISGF3. Among the remaining 121 IFN?-induced genes (150 minus 29), 73 are induced by IFN? as well as IFN?, and 48 are induced only by IFN?. Total 5 RNA samples were analyzed in duplicate on microarray chips. Untreated cells and empty vector-transfected cells were the control of IFN treated cells and Y701F-STAT1-transfected cells, respectively.
2013-09-18 | E-GEOD-50954 | biostudies-arrayexpress
Project description:Type 1 IFNs can conditionally activate all of the signal transducers and activators of transcription molecules (STATs), including STAT4. The best-characterized signaling pathways use STAT1, however, and type 1 IFN inhibition of cell proliferation is STAT1 dependent. We report that type 1 IFNs can basally stimulate STAT1- and STAT4- dependent effects in CD8 T cells, but that CD8 T cells responding to infections of mice with lymphocytic choriomenigitis virus have elevated STAT4 and lower STAT1 expression with significant consequences for modifying the effects of type 1 IFN exposure. The phenotype was associated with preferential type 1 IFN activation of STAT4 as compared to STAT1. Stimulation through the TCR induced elevated STAT4 expression, and STAT4 was required for peak expansion of antigen-specific CD8 T cells, low STAT1 levels, and resistance to type 1 IFN-mediated inhibition of proliferation. Thus, a mechanism is discovered for regulating the consequences of type 1 IFN exposure in CD8 T cells, with STAT4 acting as a key molecule in driving optimal antigen-specific responses and overcoming STAT1-dependent inhibition of proliferation. CD8 T cells were purified from uninfected WT, STAT1-deficient and STAT4-deficient mice or from D8 LCMV-infected WT mice and either control treated or treated with 1x104 U mouse IFNalpha for 90 minutes.
2012-09-07 | E-GEOD-40666 | biostudies-arrayexpress
Project description:Here we have analyzed the role of interferon regulatory factor-2 binding protein-2 (IRF2BP2) in glucocorticoid and tumor necrosis factor alpha (TNF) signaling. We used ChIP-seq to analyze chromatin binding of IRF2BP2 in glucocorticoid (dexamethasone, dex) and vehicle treated HEK293 cells expressing GR (HEK293-GR). Furthermore, we used RNA-seq to analyze how silencing of IRF2BP2 modulates transcriptional responses to dex treatment in HEK293-GR cells, and dex, TNF and co-treatment (dex and TNF, DT) in A549 cells.
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Project description:COVID-19 has rapidly circulated around the globe and caused significant morbidity and mortality. The disease is characterized by excessive production of pro-inflammatory cytokines and acute lung damage and patient mortality. Although initial cytokine cascades may be beneficial to the host for clearing the virus, enhanced production of pro-inflammatory cytokines and increasing levels in the systemic circulation, referred to as cytokine storm, can promote tissue damage by inducing inflammatory cell death in both infected and bystander cells. Of the multiple inflammatory cytokines produced by innate immune cells during SARS-CoV-2 infection, we found that the combination of TNF-α and IFN-γ specifically induced cell death characterized by GSDME¬–mediated pyroptosis, caspase-8–mediated apoptosis, and MLKL–mediated necroptosis. Cells deficient in both RIPK3 and caspase-8 or RIPK3 and FADD were resistant to this cell death. However, deletion of pyroptosis, apoptosis, or necroptosis individually was not sufficient to protect against cell death. Mechanistically, the STAT1/IRF1 axis activated by TNF-α and IFN-γ co-treatment induced iNOS for the production of nitric oxide. Pharmacological and genetic deletion of this pathway inhibited pyroptosis, apoptosis, and necroptosis in macrophages. Moreover, inhibition of inflammatory cell death protected mice from TNF-α and IFN-γ–induced lethal cytokine shock that mirrors the pathological symptoms of COVID-19. To determine the physiological relevance of protection, we neutralized both TNF-α and IFN-γ in multiple disease models associated with cytokine storm and found that this treatment provided substantial protection against not only SARS-CoV-2 infection, but also sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock models. Collectively, our findings reveal that blocking the COVID-19 cytokine-mediated inflammatory cell death signaling pathway identified in this study may benefit patients with COVID-19 or other cytokine storm-driven syndromes by limiting inflammation and tissue damage. Additionally, these results open new avenues for the treatment of other infectious and autoinflammatory diseases and cancer where TNF-α and IFN-γ synergism play key pathological roles.
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Project description:G-protein coupled receptors (GPCRs) have diverse roles in physiological processes, including immunity. Gs-coupled GPCRs increase while Gi-coupled ones decrease intracellular cAMP. Previous studies suggest that, in epithelial cells, Gs-coupled GPCRs enhance whereas Gi-coupled GPCRs suppress pro-inflammatory immune responses. In order to examine the issue, we chose beta2 adrenergic receptor and GPR40 as representatives of Gs- and Gi- coupled GPCRs, respectively, and examined their effects on TNF-alpha and IFN-gamma-(TNF-alpha + IFN-gamma) induced gene expression by HaCaT. We used microarrays to detail the global changes of gene expression induced by a beta2 adrenergic receptor agonist terbutaline or GPR40 agonist GW9508 pre-treatment in TNF-alpha + IFN-gamma - stimulated HaCaT cells.
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Project description:Expression profiling of HCT116 colon cancer cells with different treatments. Illumina HumanHT-12 V4.0 expression beadchip was used to obtain expression profiles across more than 31,000 annotated genes. Total RNA obtained from HCT116 cells with different treatments, namely, cells with TNF-α (50ng/ml)/IFN-ɣ (50U/ml) treatment, cells with TNF-α (50 ng/ml)/IFN-ɣ (50 U/ml) and silibinin (100 uM) treatment and cells without any treatment. Each sample has 2 biological replicates.
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Project description:Type 1 IFNs can conditionally activate all of the signal transducers and activators of transcription molecules (STATs), including STAT4. The best-characterized signaling pathways use STAT1, however, and type 1 IFN inhibition of cell proliferation is STAT1 dependent. We report that type 1 IFNs can basally stimulate STAT1- and STAT4- dependent effects in CD8 T cells, but that CD8 T cells responding to infections of mice with lymphocytic choriomenigitis virus have elevated STAT4 and lower STAT1 expression with significant consequences for modifying the effects of type 1 IFN exposure. The phenotype was associated with preferential type 1 IFN activation of STAT4 as compared to STAT1. Stimulation through the TCR induced elevated STAT4 expression, and STAT4 was required for peak expansion of antigen-specific CD8 T cells, low STAT1 levels, and resistance to type 1 IFN-mediated inhibition of proliferation. Thus, a mechanism is discovered for regulating the consequences of type 1 IFN exposure in CD8 T cells, with STAT4 acting as a key molecule in driving optimal antigen-specific responses and overcoming STAT1-dependent inhibition of proliferation.
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