The role of nuclear receptors in regulation of Th17/Treg biology and its implications for diseases

Park, Benjamin V.; Fan, Ping

doi:10.1038/cmi.2015.21

Cited by 46 publications

(27 citation statements)

References 109 publications

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“…Median expression levels of HLA-G were about half compared to HIF1A , and VEGFA and similar to that reported for FOXP3 , a key nuclear transcription factor induced by HIF-1 important in adaptive immune responses for regulatory T cells (Tregs) recruited at inflammatory hypoxic sites [64]. IL-17A is a hallmark of helper CD4 + T-cell type 17 lymphocytes that infiltrate human CRCs: the density of these cells has been correlated with a poor prognosis in CRC [65, 66]. IL17A expression levels were reported only for COAREAD cohort and were lower with respect to all the other markers.…”

Section: Evidences Of Hla-g Balanced Expression Through Hif-1 In Tsupporting

confidence: 54%

Hypoxic Modulation of HLA-G Expression through the Metabolic Sensor HIF-1 in Human Cancer Cells

Garziera

Scarabel

Toffoli

2017

Journal of Immunology Research

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The human leukocyte antigen-G (HLA-G) is considered an immune checkpoint molecule involved in tumor immune evasion. Hypoxia and the metabolic sensor hypoxia-inducible factor 1 (HIF-1) are hallmarks of metastasization, angiogenesis, and intense tumor metabolic activity. The purpose of this review was to examine original in vitro studies carried out in human cancer cell lines, which reported data about HLA-G expression and HIF-1 mediated-HLA-G expression in response to hypoxia. The impact of HLA-G genomic variability on the hypoxia responsive elements (HREs) specific for HIF-1 binding was also discussed. Under hypoxia, HLA-G-negative cell lines might transcribe HLA-G without translation of the protein while in contrast, HLA-G-positive cell lines, showed a reduced HLA-G transcriptional activity and protein level. HIF-1 modulation of HLA-G expression induced by hypoxia was demonstrated in different cell lines. HLA-G SNPs rs1632947 and rs41551813 located in distinct HREs demonstrated a prominent role of HIF-1 binding by DNA looping. Our research revealed a fine regulation of HLA-G in hypoxic conditions through HIF-1, depending on the cellular type and HLA-G genomic variability. Specifically, SNPs found in HREs should be considered in future investigations as markers with potential clinical value especially in metastatic malignancies.

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Section: Evidences Of Hla-g Balanced Expression Through Hif-1 In Tsupporting

confidence: 54%

Hypoxic Modulation of HLA-G Expression through the Metabolic Sensor HIF-1 in Human Cancer Cells

Garziera

Scarabel

Toffoli

2017

Journal of Immunology Research

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“…Tregs have powerful effects and maintain immune tolerance. These cells are induced by interleukin (IL)-2, transforming growth factor-β (TGF-β) and forkhead box protein 3 (Foxp3), a specific marker of Treg maturation and function [6, 7]. In contrast, Th17 cells, which produce the cytokine IL-17, display proinflammatory effects.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, Th17 cells, which produce the cytokine IL-17, display proinflammatory effects. The transcription factor retinoid- related orphan receptor (ROR)-γt and the inflammatory cytokine IL-6 induce Th17 cell differentiation [6, 7]. Notably, imbalance in the Treg/Th17 ratio may influence disease progression [8].…”

Section: Introductionmentioning

confidence: 99%

Glycyrrhizin, a High-Mobility Group Box 1 Inhibitor, Improves Lipid Metabolism and Suppresses Vascular Inflammation in Apolipoprotein E Knockout Mice

et al. 2018

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Background: High-mobility group box protein 1 (HMGB1) is known to have proinflammatory properties; however, the mechanisms by which HMGB1 influences immune responses during atherosclerosis (AS) development are not well understood. Thus, this study investigated the relationship between HMGB1 and vascular inflammation in Apoe^–/– mice and whether glycyrrhizin (GLY), a small inhibitor of HMGB1, could have atheroprotective effects in AS. Methods: Apoe^–/– mice on a high-fat diet were treated with GLY (50 mg/kg) or vehicle by gavage once daily for 12 weeks, respectively. Results: The GLY group exhibited significantly decreased serum lipid levels, atherosclerotic plaque deposition, and serum HMGB1 levels, as well as an increased Treg/Th17 ratio. The GLY group displayed increased interleukin-10 (IL-10) and IL-2 expression and decreased IL-17A and IL-6 expression. Furthermore, the GA treatment significantly reduced STAT3 phosphorylation in Th17 cells and increased STAT5 phosphorylation in Treg cells. Conclusions: Our findings indicate that the attenuation of atherosclerotic lesions in Apoe^–/– mice by GLY might be associated with the amelioration of lipid metabolism abnormalities, inhibition of HMGB1 expression, and alterations in the Treg/Th17 ratio.

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“…1). Additional transcription factors, such as the nuclear receptor 4A (NR4A) family, transcription regulator protein BACH2, RUNX proteins, retinoic acid receptors and aryl hydrocarbon receptor (AHR), clearly have essential roles in the maintenance of polarized states, as the disruption of these transcription factors leads to enhanced plasticity between subsets 43,[121][122][123][124][125] . Nevertheless, even the expression of a suite of transcription factors is not sufficient to drive the transcriptional programmes of T helper cell subsets because access of the transcription factors to their DNA-binding sites in the genome is regulated.…”

Section: Box 2 | Phenotypic Plasticity In Inflammatory and Regulatorymentioning

confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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| CD4 + T cells differentiate and acquire distinct functions to combat specific pathogens but can also adapt their functions in response to changing circumstances. Although this phenotypic plasticity can be potentially deleterious, driving immune pathology, it also provides important benefits that have led to its evolutionary preservation. Here, we review CD4 + T cell plasticity by examining the molecular mechanisms that regulate it -from the extracellular cues that initiate and drive cells towards varying phenotypes, to the cytosolic signalling cascades that decipher these cues and transmit them into the cell and to the nucleus, where these signals imprint specific gene expression programmes. By understanding how this functional flexibility is achieved, we may open doors to new therapeutic approaches that harness this property of T cells.

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The role of nuclear receptors in regulation of Th17/Treg biology and its implications for diseases

Cited by 46 publications

References 109 publications

Hypoxic Modulation of HLA-G Expression through the Metabolic Sensor HIF-1 in Human Cancer Cells

Hypoxic Modulation of HLA-G Expression through the Metabolic Sensor HIF-1 in Human Cancer Cells

Glycyrrhizin, a High-Mobility Group Box 1 Inhibitor, Improves Lipid Metabolism and Suppresses Vascular Inflammation in Apolipoprotein E Knockout Mice

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

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