Role of Tumor Necrosis Factor-α in the Human Systemic Endotoxin-Induced Transcriptome

Scicluna, Brendon P.; Veer, Cornelis van ’t; Nieuwdorp, Max; Felsmann, Karen; Wlotzka, Britta; Stroes, Erik S.G.; Poll, Tom van der

doi:10.1371/journal.pone.0079051

Cited by 18 publications

(25 citation statements)

References 49 publications

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“…This fraction increased to more than 24% of the studied genes when a less stringent FDR threshold of < 0.05 was applied. The magnitude of this effect was in accordance with previous reports using genome-wide expression analyses demonstrating that LPS strongly affects the transcriptomic profile of blood cells revealed by in vitro and in vivo studies in humans [62, 63, 71–74]. …”

Section: Discussionsupporting

confidence: 91%

LPS-induced modules of co-expressed genes in equine peripheral blood mononuclear cells

et al. 2017

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BackgroundLipopolysaccharide (endotoxin, LPS) is a strong inducer of the innate immune response. It is widespread in our environment, e.g. in house dust and contributes to asthma. Compared to humans, horses are even more sensitive to LPS. However, data on LPS effects on the equine transcriptome are very limited. Using RNA-seq we analysed LPS-induced differences in the gene expression in equine peripheral blood mononuclear cells at the gene and gene-network level in two half-sib families and one group of unrelated horses.Results24 h-LPS challenge of equine immune cells resulted in substantial changes in the transcriptomic profile (1,265 differentially expressed genes) showing partial overlap with human data. One of the half-sib families showed a specific response different from the other two groups of horses. We also identified co-expressed gene modules that clearly differentiated 24 h-LPS- from non-stimulated samples. These modules consisted of 934 highly interconnected genes and included genes involved in the immune response (e.g. IL6, CCL22, CXCL6, CXCL2), however, none of the top ten hub genes of the modules have been annotated as responsive to LPS in gene ontology.ConclusionsUsing weighted gene co-expression network analysis we identified ten co-expressed gene modules significantly regulated by in vitro stimulation with LPS. Apart from 47 genes (5%) all other genes highly interconnected within the most up- and down-regulated modules were also significantly differentially expressed (FDR < 0.05). The LPS-regulated module hub genes have not yet been described as having a role in the immune response to LPS (e.g. VAT1 and TTC25).Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3390-y) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 91%

LPS-induced modules of co-expressed genes in equine peripheral blood mononuclear cells

et al. 2017

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“…Probes were collapsed to gene symbols for data presentation and interpretation. Bioinformatic analysis for biofunctional and canonical signaling pathways was performed by means of the Ingenuity Pathway Analysis software (www.ingenuity.com), as previously described (20). All parameters were kept as default.…”

Section: Microarray Data Analysis and Bioinformaticsmentioning

confidence: 99%

IFN-γ Priming of Macrophages Represses a Part of the Inflammatory Program and Attenuates Neutrophil Recruitment

Hoeksema

Scicluna

Boshuizen

et al. 2015

The Journal of Immunology

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Macrophages form a heterogeneous population of immune cells, which is critical for both the initiation and resolution of inflammation. They can be skewed to a proinflammatory subtype by the Th1 cytokine IFN-γ and further activated with TLR triggers, such as LPS. In this work, we investigated the effects of IFN-γ priming on LPS-induced gene expression in primary mouse macrophages. Surprisingly, we found that IFN-γ priming represses a subset of LPS-induced genes, particularly genes involved in cellular movement and leukocyte recruitment. We found STAT1-binding motifs enriched in the promoters of these repressed genes. Furthermore, in the absence of STAT1, affected genes are derepressed. We also observed epigenetic remodeling by IFN-γ priming on enhancer or promoter sites of repressed genes, which resulted in less NF-κB p65 recruitment to these sites without effects on global NF-κB activation. Finally, the epigenetic and transcriptional changes induced by IFN-γ priming reduce neutrophil recruitment in vitro and in vivo. Our data show that IFN-γ priming changes the inflammatory repertoire of macrophages, leading to a change in neutrophil recruitment to inflammatory sites.

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“…In the context of severe infection leading to organ failure (sepsis and septic shock), median levels of systemic LPS levels in patients were estimated at 20 ng/kg . LPS induces substantial alterations to leukocyte cell composition as well as gene transcription . In the early phase of human endotoxemia, monocytes and lymphocytes typically diminish in numbers, whereas neutrophil counts increase dramatically.…”

Section: Introductionmentioning

confidence: 99%

Leukocyte transcriptional signatures dependent on LPS dosage in human endotoxemia

Khan

Perlee

Schoenmaker

et al. 2019

Journal of Leukocyte Biology

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The host immune response is characterized by a complex interplay of signal‐specific cellular transcriptional responses. The magnitude of the immune response is dependent on the strength of the external stimulus. Knowledge on leukocyte transcriptional responses altered in response to different stimulus dosages in man is lacking. Here, we sought to identify leukocyte transcriptional signatures dependent on LPS dose in humans. Healthy human volunteers were administered 1 ng/kg (n = 7), 2 ng/kg (n = 6), or 4 ng/kg (n = 7) LPS intravenously. Blood was collected before (pre‐LPS) and 4 h after LPS administration. Total RNA was analyzed by microarrays and generalized linear models. Pathway analysis was performed by using Ingenuity pathway analysis. Leukocyte transcriptomes altered per LPS dosage were predominantly shared, with 47% common signatures relative to pre‐LPS. A univariate linear model identified a set of 3736 genes that exhibited a dependency on differing LPS dosages. Neutrophil, monocyte, and lymphocyte counts explained 38.9% of the variance in the LPS dose‐dependent gene set. A multivariate linear model including leukocyte composition delineated a set of 295 genes with a dependency on LPS dose. Evaluation of the 295 gene signature in patients with sepsis due to abdominal infections showed significant correlations. Promoter regions of the LPS dose gene set were enriched for YY1, EGR1, ELK1, GABPA, KLF4, and REL transcription factor binding sites. Intravenous injection of 1, 2, or 4 ng/kg LPS was accompanied by both shared and distinct leukocyte transcriptional alterations. These data may assist in assessing the severity of the insult in patients with abdominal sepsis.

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Role of Tumor Necrosis Factor-α in the Human Systemic Endotoxin-Induced Transcriptome

Cited by 18 publications

References 49 publications

LPS-induced modules of co-expressed genes in equine peripheral blood mononuclear cells

LPS-induced modules of co-expressed genes in equine peripheral blood mononuclear cells

IFN-γ Priming of Macrophages Represses a Part of the Inflammatory Program and Attenuates Neutrophil Recruitment

Leukocyte transcriptional signatures dependent on LPS dosage in human endotoxemia

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