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The Cytokines IL-21 and GM-CSF have Opposing Regulatory Roles in the Apoptosis of Conventional Dendritic Cells

ABSTRACT: Interleukin-21 (IL-21) has broad actions on T- and B-cells, but its actions in innate immunity are poorly understood. Here we show that IL-21 induced apoptosis of conventional dendritic cells (cDCs) via STAT3 and Bim, and this was inhibited by granulocyte-macrophage colony-stimulating factor (GM-CSF). ChIP-Seq analysis revealed genome-wide binding competition between GM-CSF-induced STAT5 and IL-21-induced STAT3. Expression of IL-21 in vivo decreased cDC numbers, and this was prevented by GM-CSF. Moreover, repetitive M-NM-1-galactosylceramide injection of mice induced IL-21 but decreased GM-CSF production by natural killer T (NKT) cells, correlating with decreased cDC numbers. Furthermore, adoptive-transfer of wild-type CD4+ T cells caused more severe colitis with increased DCs and interferon (IFN)-M-NM-3-producing CD4+ T cells in Il21r-/-Rag2-/- mice (which lack T cells and have IL-21-unresponsive DCs) than in Rag2-/- mice. Thus, IL-21 and GM-CSF exhibit cross-regulatory actions on gene regulation and apoptosis, regulating cDC numbers and thereby the magnitude of the immune response. Total 6 samples were examined. Splenic dendritic cells were treated with IL-21 and/or GM-CSF studying STAT3 and STAT5B binding in the genome

ORGANISM(S): Mus musculus

SUBMITTER: Peng Li

PROVIDER: E-GEOD-27161 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The Cytokines IL-21 and GM-CSF have Opposing Regulatory Roles in the Apoptosis of Conventional Dendritic Cells

Project description:Interleukin-21 (IL-21) has broad actions on T- and B-cells, but its actions in innate immunity are poorly understood. Here we show that IL-21 induced apoptosis of conventional dendritic cells (cDCs) via STAT3 and Bim, and this was inhibited by granulocyte-macrophage colony-stimulating factor (GM-CSF). ChIP-Seq analysis revealed genome-wide binding competition between GM-CSF-induced STAT5 and IL-21-induced STAT3. Expression of IL-21 in vivo decreased cDC numbers, and this was prevented by GM-CSF. Moreover, repetitive α-galactosylceramide injection of mice induced IL-21 but decreased GM-CSF production by natural killer T (NKT) cells, correlating with decreased cDC numbers. Furthermore, adoptive-transfer of wild-type CD4+ T cells caused more severe colitis with increased DCs and interferon (IFN)-γ-producing CD4+ T cells in Il21r-/-Rag2-/- mice (which lack T cells and have IL-21-unresponsive DCs) than in Rag2-/- mice. Thus, IL-21 and GM-CSF exhibit cross-regulatory actions on gene regulation and apoptosis, regulating cDC numbers and thereby the magnitude of the immune response.

2013-02-14 | GSE27161 | GEO

Opposing Roles of STAT1 and STAT3 in IL-21 Function in CD4+ T cells

Project description:Interleukin-21 (IL-21) is a type 1 cytokine essential for immune cell differentiation and function. Although IL-21 can activate several STAT family transcription factors, previous studies focused mainly on the role of STAT3 in IL-21 signaling. Here, we investigated the role of STAT1 and show that STAT1 and STAT3 have at least partially opposing roles in IL-21 signaling in CD4+ T cells. IL-21 induced STAT1 phosphorylation, and this was augmented in Stat3-deficient CD4+ T cells. RNA-Seq analysis of CD4+ T cells from Stat1- and Stat3-deficient mice revealed that both STAT1 and STAT3 are critical for IL-21-mediated gene regulation. Expression of some genes, including Tbx21 and Ifng, was differentially regulated by STAT1 and STAT3, and interestingly, ChIP-Seq analysis showed that STAT3 binding at Tbx21 and Ifng loci was attenuated in Stat1-deficient cells. Moreover, opposing actions of STAT1 and STAT3 on IFN- expression in CD4+ T cells were demonstrated in vivo during chronic lymphocytic choriomeningitis (LCMV) infection. Finally, IL-21-mediated induction of STAT1 phosphorylation, as well as IFNG and TBX21 expression, were higher in CD4+ T cells from patients with autosomal dominant hyper-IgE syndrome (AD-HIES), which is caused by STAT3 deficiency. These data indicate an interplay between STAT1 and STAT3 in fine-tuning IL-21 actions. Genome-wide transcription factors mapping and binding of STAT3 in mouse CD4+ T cells in both WT and Stat1-deficient mice. RNA-Seq is performed in mouse CD4+ T cells in WT, Stat1-deficient and Stat3-deficient mice.

2015-07-01 | E-GEOD-63204 | biostudies-arrayexpress

Opposing Roles of STAT1 and STAT3 in IL-21 Function in CD4+ T cells

2015-07-01 | GSE63204 | GEO

Microarray analysis of WT bone marrow myeloid progenitors, BM cultured with GM-CSF and M-CSF, and monocytes treated with GM-CSF

Project description:Analysis of genes induced in DC precursors and in BM cells and monocytes treated with GM-CSF For progenitor arrays, bone marrow progenitors (CMP, GMP, CDP, and pre-cDC) were harvested from WT C57Bl/6 mice. For culture arrays, BM was cultured in the presence of GM-CSF or M-CSF and adherent and non-adherent cells sorted. For monocyte cultures, sorted BM monocytes were treated with GM-CSF for 0, 24 or 48 hours.

2012-05-20 | E-GEOD-37029 | biostudies-arrayexpress

Human Eosinophils Express a Distinct Gene Expression Program in Response to IL-3 Compared to Common Beta-Chain Cytokines IL-5 and GM-CSF

Project description:Background: Despite recent advances in asthma management with anti-IL-5 therapies, many patients with eosinophilic asthma remain poorly controlled. IL-3 shares a common beta subunit receptor with both IL-5 and GM-CSF, but through alpha subunit-specific properties, uniquely influences eosinophil biology and may serve as a potential therapeutic target. Objective: We aimed to globally characterize the transcriptomic profiles of GM-CSF, IL-3, and IL-5 stimulation and identify differences in gene expression using advanced statistical modeling. Methods: Human eosinophils were isolated from the peripheral blood of healthy volunteers and stimulated with either GM-CSF, IL-3 or IL-5 for 48 hours. RNA was then extracted and bulk sequencing performed. DESeq analysis identified differentially expressed genes and weighted gene co-expression network analysis independently defined modules of genes that are highly co-expressed. Results: IL-3 stimulation yielded the most numbers of differentially expressed genes that were also highly co-expressed. GM-CSF and IL-5 stimulation demonstrated redundancy in eosinophil gene expression. Conclusion: IL-3 produces a distinct eosinophil gene expression program among the beta-chain receptor cytokines.

2019-09-06 | GSE128027 | GEO

Effect of metronidazole on microglial gene expression and gut microbiome composition in the 5XFAD mice model of Alzheimer's disease

Project description:The gut microbiota and innate immune system play critical roles in Alzheimer’s disease (AD). Bacteroides is elevated in AD patients and correlates with cerebrospinal fluid levels of Aβ and tau. We found that increased amyloid-β (Aβ) plaques in Bacteroides fragilis treated APP/PS1-21 mice were associated with altered cortical expression Aβ processing genes. B. fragilis suppressed peripheral CD4+ T cell production of GM-CSF and IL-4 and transcriptional changes in microglia related to GM-CSF and IL-4 signaling, phagocytosis, and protein degradation. Furthermore, B. fragilis impaired the microglial uptake of intracranially injected Aβ42, whereas Erysipelotrichaceae strains increased uptake. Depleting murine Bacteroidetes with metronidazole decreased amyloid load in aged 5xFAD mice, increased CD4+ T cell GM-CSF production, and activated microglial pathways related to cytokine signaling, phagocytosis and lysosomal degradation. These data suggest that the gut microbiome may contribute to AD pathogenesis by suppressing peripheral cytokines and microglia phagocytic function, leading to impaired immune-mediated Aβ clearance.

2024-10-12 | GSE215439 | GEO

Effect of Bacteroides fragilis administration on microglia in WT and the APP-PS1 model of Alzheimer's disease [Bfrag]

2024-10-12 | GSE215438 | GEO

Expression data from MDSC treated with STAT3 inhibitor Napabucasin

Project description:MDSC (myeloid-derived suppressor cells) were generated in vitro using IL-6 and GM-CSF. To identify the role of STAT3 in MDSC, we treated the generated cells for 24 hours with DMSO (control) or 1 µM STAT3 inhibitor Napabucasin (also known as BBI608) and compared their expression profile by microarray. We found genes and pathways that are up- or downregulated upon STAT3 inhibition in MDSC.

2022-03-23 | GSE189147 | GEO

Dusp9 expression and function in dendritic cells

Project description:Plasmacytoid dendritic cells (pDC) efficiently produce large amounts of type I interferon in response to TLR7 and TLR9 ligands, whereas conventional DCs (cDC) predominantly secrete high levels of the cytokines IL-10 and IL-12. The molecular basis underlying this distinct phenotype is not well understood. Here, we identified the MAPK phosphatase Dusp9/MKP-4 by transcriptome analysis as selectively expressed in pDC, but not cDC. We confirmed the constitutive expression of Dusp9 at the protein level in pDC generated in vitro by culture with Flt3L and ex vivo in sorted splenic pDC. Dusp9 expression was low in B220- bone marrow precursors and was up-regulated during pDC differentiation, concomitant with established pDC markers. Higher expression of Dusp9 in pDC correlated with impaired phosphorylation of the MAPK ERK1/2 upon TLR9 stimulation. Notably, Dusp9 was not expressed at detectable levels in human pDC, although these displayed similarly impaired activation of ERK1/2 MAPK compared to cDC. Enforced retroviral expression of Dusp9 in mouse GM-CSF-induced cDC increased the expression of TLR7/9-induced IL-12p40 and IFNwhereas IL-10 levels were diminished. Taken together, our results suggest that the species-specific, selective expression of Dusp9 in murine pDC contributes to the differential cytokine/interferon output of pDC and cDC. pDC and cDC subsets were purified from mouse spleens to high purity and analysed by Affymetrix GeneChips.

2015-06-26 | E-GEOD-54120 | biostudies-arrayexpress

Expression data from in vitro differentiated MDSC

Project description:MDSC (myeloid-derived suppressor cells) can be differentiated in vitro using IL-6 and GM-CSF. To identify the specific role of IL-6 in this process, we used microarray to compare MDSC differentiated with IL-6 and GM-CSF to MDSC differentiated with GM-CSF alone. We have found genes and pathways that are up- or downregulated when IL-6 is present.

2020-08-19 | GSE148293 | GEO

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