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Exogenous Interleukin-10 versus Glucocorticoids: Effect on Gene Expression and Pro-inflammatory Cytokine Release in Polymorphonuclear Leukocytes and Monocytes of the Newborn

ABSTRACT: INTRODUCTION: Persistent lung inflammation, with an influx of polymorphonuclear leukocytes and monocytes, occurs early in bronchopulmonary dysplasia. We hypothesized that: 1) that interleukin-10, a potent anti-inflammatory cytokine, would cause a markedly different gene expression profile compared to dexamethasone in these cells, and 2) monocyte insensitivity to dexamethasone was related to glucocorticoid receptor expression. RESULTS: For polymorphonuclear leukocytes, there were <20% of genes changing expression in common between interleukin-10 and dexamethasone. The monocyte had 5 times the number of genes changing expression with interleukin-10 compared to the polymorphonuclear leukocyte. Dexamethasone, in the therapeutic range, had no effect on gene expression in monocytes. The order of potency for inhibition of interleukin-8 release from monocytes was IL-10>betamethasone>> dexamethasone and hydrocortisone. Glucocorticoid potency was directly related to the degree of glucocorticoid receptor translocation to the monocyte nucleus. DISCUSSION: Gene expression profiles by IL-10 versus dexamethasone indicates that there may be major differences in efficacy and adverse effects if interleukin-10 is used for therapy in the future. Betamethasone may be a better therapeutic choice than dexamethasone. METHODS: Isolated cord blood cells were pre-incubated with anti-inflammatory agents prior to endotoxin stimulation. Measurements were made by microarrays, RT-qPCR, ELISA, and Western blots.

ORGANISM(S): Homo sapiens

PROVIDER: GSE35683 | GEO | 2012/02/16

SECONDARY ACCESSION(S): PRJNA152409

REPOSITORIES: GEO

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Exogenous Interleukin-10 versus Glucocorticoids: Effect on Gene Expression and Pro-inflammatory Cytokine Release in Polymorphonuclear Leukocytes and Monocytes of the Newborn

Project description:INTRODUCTION: Persistent lung inflammation, with an influx of polymorphonuclear leukocytes and monocytes, occurs early in bronchopulmonary dysplasia. We hypothesized that: 1) that interleukin-10, a potent anti-inflammatory cytokine, would cause a markedly different gene expression profile compared to dexamethasone in these cells, and 2) monocyte insensitivity to dexamethasone was related to glucocorticoid receptor expression. RESULTS: For polymorphonuclear leukocytes, there were <20% of genes changing expression in common between interleukin-10 and dexamethasone. The monocyte had 5 times the number of genes changing expression with interleukin-10 compared to the polymorphonuclear leukocyte. Dexamethasone, in the therapeutic range, had no effect on gene expression in monocytes. The order of potency for inhibition of interleukin-8 release from monocytes was IL-10>betamethasone>> dexamethasone and hydrocortisone. Glucocorticoid potency was directly related to the degree of glucocorticoid receptor translocation to the monocyte nucleus. DISCUSSION: Gene expression profiles by IL-10 versus dexamethasone indicates that there may be major differences in efficacy and adverse effects if interleukin-10 is used for therapy in the future. Betamethasone may be a better therapeutic choice than dexamethasone. METHODS: Isolated cord blood cells were pre-incubated with anti-inflammatory agents prior to endotoxin stimulation. Measurements were made by microarrays, RT-qPCR, ELISA, and Western blots. Isolation of cord blood polymorphonuclear leukocytes and monocytes separately from 5 subjects. Endotoxin stimulation in cell culture for 4 hours. Comparison of gene expression between endotoxin alone versus endotoxin-stimualted cells pretreated with interleukin-10 or dexamethasone (at equimolar, therapeutic levels, 10-8 M. Cell Types : MONOs, PMNs; Treatments: LPS, LPS+IL-10, LPS+DEX

2012-02-16 | E-GEOD-35683 | biostudies-arrayexpress

Gene Expression Profile of Endotoxin-stimulated Leukocytes of the Newly Born: Control of Cytokine Gene Expression by Interleukin-10.

Project description:Introduction: Increasing evidence now supports the association between the fetal inflammatory response syndrome (FIRS) with the pathogenesis of preterm labor, intraventricular hemorrhage and bronchopulmonary dysplasia. These disorders are among the most important causes of mortality and morbidity in the perinatal period. During the fetal inflammatory response syndrome (FIRS) polymorphonuclear leukocytes (PMNs) and monocytes (MONOs) are sequentially recruited into the placenta; the same process occurs in the lung of the newborn during the development of bronchopulmonary dysplasia (BPD). The aim of the study was to reveal cell-specific differences in gene expression and cytokine release in response to endotoxin that would elucidate inflammatory control mechanisms in the newly born. Results: Compared to PMNs, MONOs had a greater diversity and more robust expression of pro-inflammatory (PI) gene expression at 4h. Only MONOs had genes changing expression in the JAK/STAT pathway including interleukin-10. Isolation of cord blood polymorphonuclear leukocytes and monocytes separately from 5 subjects. Endotoxin stimulation in cell culture for 4 hours. Comparison of gene expression between PBS versus endotoxin (LPS).

2012-08-02 | E-GEOD-39840 | biostudies-arrayexpress

The life-saving benefit of dexamethasone in severe COVID-19 is linked to a reversal of monocyte dysregulation

Project description:Dexamethasone is a life-saving treatment for severe COVID-19, yet its mechanism of action is unknown, and many patients deteriorate or die despite timely treatment initiation. Here, we identify dexamethasone treatment-induced cellular and molecular changes associated with improved survival in COVID-19 patients. We observed a reversal of transcriptional hallmark signatures in monocytes associated with severe COVID-19 and the induction of a monocyte substate characterized by the expression of glucocorticoid-response genes. These molecular responses to dexamethasone were detected in circulating and pulmonary monocytes, and they were directly linked to survival. Monocyte single-cell RNA sequencing (scRNA-seq)-derived signatures were enriched in whole blood transcriptomes of patients with fatal outcome in two independent cohorts, highlighting the potential for identifying non-responders refractory to dexamethasone. Our findings link the effects of dexamethasone to specific immunomodulation and reversal of monocyte dysregulation, and they highlight the potential of single-cell omics for monitoring in vivo target engagement of immunomodulatory drugs and for patient stratification for precision medicine approaches.

2024-07-04 | GSE270901 | GEO

Homo sapiens

Project description:Exogenous Interleukin-10 versus Glucocorticoids: Effect on Gene Expression and Pro-inflammatory Cytokine Release in Polymorphonuclear Leukocytes and Monocytes of the Newborn

| PRJNA152409 | ENA

Extensive epigenomic integration of the glucocorticoid response in primary human monocytes and in vitro derived macrophages

Project description:Glucocorticoid receptor is a transcription factor that is ubiquitously expressed. Glucocorticoids are circadian steroids that regulate a wide range of bodily functions, including immunity. Here we report that synthetic glucocorticoids affect 1035 mRNAs in isolated healthy human blood monocytes but only 165 in the respective six day-old monocyte-derived macrophages. The majority of the glucocorticoid response in monocytes concerns genes that are dynamic upon monocyte to macrophage differentiation, whereby macrophage-like mRNA levels are often reached in monocytes within four hours of treatment. Concomitantly, over 5000 chromosomal H3K27ac regions undergo remodelling, of which 60% involve increased H3K27ac signal. We find that chromosomal glucocorticoid receptor binding sites correlate with positive but not with negative local epigenomic effects. To investigate further we assigned our data to topologically associating domains (TADs). This shows that about 10% of macrophage TADs harbour at least one GR binding site and that half of all the glucocorticoid-induced H3K27ac regions are confined to these TADs. Our analyses are therefore consistent with the notion that TADs naturally accommodate information from sets of distal glucocorticoid response elements.

2019-03-03 | GSE109440 | GEO

Gene Expression Profile of Endotoxin-stimulated Leukocytes of the Newly Born: Control of Cytokine Gene Expression by Interleukin-10.

2012-08-03 | GSE39840 | GEO

Effect of glucocorticoid chemical structure and receptor potency on human trabecular meshwork cells

Project description:Glucocorticoids with different chemical structures but similar glucocorticoid receptor potency regulate subsets of common and unique genes in human trabecular meshwork cells. Gene expression changes of human trabecular meshwork cells, TM 86 and TM 93, due to treatment with dexamethasone (Dex), fluocinolone acetonide (FA), and triamcinolone acetonide (TA).

2010-02-15 | GSE16643 | GEO

Postnatal glucocorticoids suppress myelination in a dose-dependent manner by genomic mechanism

Project description:Objective: Postnatal glucocorticoids (GCs) are widely used in the prevention of chronic lung disease in premature infants. However, their use is associated with neurodevelopmental delay and cerebral palsy. We hypothesized that postnatal dexamethasone or betamethasone in high-dose, but not low-dose, would induce hypomyelination, astrogliosis, and motor impairment in premature rabbit pups. Additionally, these effects would be mediated by glucocorticoid receptors (GRs). Methods: Preterm rabbit pups, delivered by C-section at E29 (term=32d), were treated with a high dose of dexamethasone or vehicle. Myelin basic protein (MBP), glial fibrillary basic protein (GFAP), oligodendrocyte proliferation and maturation, and alteration of transcriptomic profile were evaluated in these pups. Neurobehavioral assessments were performed at 14d. Results: High-dose dexamethasone treatment reduced MBP expression and induced motor-impairment compared with controls. High-dose dexamethasone induced astrogliosis and altered genes associated with myelination, cell-cycle, GR, and MAP-Kinase signaling. Interpretation: High-dose postnatal dexamethasone arrested maturation of oligodendrocytes, and induced hypomyelination, gliosis and motor deficits. GC treatment reduced myelination by genomic GR-dependent mechanisms, and caused astrogliosis by non-genomic mechanisms. Two-condition experiment: forebrains of HDD (high dose dexamethasone) vs. CTR (PBS) post-natally expossed rabbit pups. Biological replicates: 4 CTR replicates, 4 HDD replicates.

2013-02-27 | E-GEOD-44610 | biostudies-arrayexpress

Engineered IL-10 variants elicit potent immuno-modulatory activities at therapeutic low ligand doses

Project description:Interleukin-10 is a dimeric cytokine with potent anti-inflammatory and anti-cancer activities. Despite its immune-regulatory potential, IL-10-based therapies have shown only marginal benefits in the clinic. Here we have explored whether the stability of the IL-10-receptor complex contributes to IL-10 immuno-modulatory potency. For that, we have generated an IL-10 mutant with greatly enhanced affinity for its IL-10Rβ receptor via yeast surface display. The affinity enhanced IL-10 variants formed surface active complexes more efficiently than the wild-type cytokine and triggered more potent STAT1 and STAT3 activation in human monocytes and CD8 T cells. This in turn led to more robust induction of IL-10-mediated gene expression programs at a wide range of ligand concentrations in both human cell subsets. IL-10 regulated genes involved in monocyte energy homeostasis, migration and trafficking, and genes involved in CD8 T cell exhaustion. Interestingly, at non-saturating doses, IL-10 lost key components of its gene-expression program, which may explain its lack of efficacy in a clinical set up. Remarkably, our engineered IL-10 variant exhibited a more robust bioactivity profile than IL-10 wt at all the doses tested in monocytes and CD8 T cells. Our study provides unique insights into how IL-10-receptor complex stability contributes to fine-tune IL-10 biology, and open new opportunities to revitalize failed IL-10 therapies.

2020-09-15 | GSE146438 | GEO

Antagonism between glucocorticoid and both GM-CSF and M-CSF

Project description:In this study, we compared human monocytes treated with GM-CSF, M-CSF, dexamethosone or in combination with dexamethasone. A comparison of the different monocyte populations was made using microarray profiling.

2014-05-01 | E-MTAB-2212 | biostudies-arrayexpress

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