Progesterone regulates HLA-G gene expression through a novel progesterone response element

Yie, Shang-mian; Xiao, Rong; Librach, Clifford L.

doi:10.1093/humrep/del126

Cited by 82 publications

(77 citation statements)

References 32 publications

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“…Progesterone has been recently demonstrated to enhance HLA-G expression in the JEG-3 choriocarcinoma cell line and isolated first-trimester cytotrophoblasts 14 through receptor activation followed by binding to a progesterone response element, which shares 60% homology to the wild-type mouse mammary tumor virus progesterone response element sequence. 15 Furthermore, progesterone receptors are present in human heart as well as vascular endothelial and smooth muscle cells, 24,25 indicating that these tissues are possible targets for progesterone-induced HLA-G expression. Intriguingly, our results show induction of this expression after treatment with progesterone and partial inhibition after coincubation with mifepristone in HCAEC, HAEC, and …”

Section: Discussionmentioning

confidence: 99%

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Progesterone Induces Human Leukocyte Antigen-G Expression in Vascular Endothelial and Smooth Muscle Cells

et al. 2008

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Background-Human leukocyte antigen-G (HLA-G) expression in heart transplant patients has been negatively associated with acute cellular rejection and cardiac allograft vasculopathy. We assessed HLA-G expression in vascular human endothelial and smooth muscle cell cultures to determine if future therapeutic agents can be targeted toward inducing HLA-G expression to protect against allograft rejection and vasculopathy. Methods and Results-Human coronary artery endothelial, aortic endothelial, and coronary artery smooth muscle cell cultures were exposed to cytokines (interferon-␥ or interleukin-10), hypoxia/reoxygenation stress, immunosuppressive agents (cyclosporine, sirolimus, or tacrolimus), or progesterone. HLA-G was not expressed by untreated, normoxic cells. Furthermore, maximal doses of interferon-␥, interleukin-10, cyclosporine, sirolimus, or tacrolimus, as well as exposure to hypoxia/reoxygenation, failed to induce HLA-G expression. HLA-G, which has previously not been detected in adult vascular endothelial and smooth muscle cells, was detected by enzyme-linked immunosorbent assay and flow cytometry in human coronary artery endothelial, human coronary aortic endothelial, and human coronary artery smooth muscle cultures after incubation with progesterone in a dose-dependent manner (PϽ0.001) with no change in cellular proliferation ability or viability. This effect was partially blocked in the presence of mifepristone, a progesterone receptor antagonist (human coronary artery endothelial: 48.8Ϯ15.6%; human coronary aortic endothelial: 59.5Ϯ9.5%; human coronary artery smooth muscle: 59.8Ϯ9.8% of control; PϽ0.05). Progesterone-induced HLA-G expression was not protective against hypoxia/reoxygenation injury. Conclusions-HLA-G is not expressed at baseline in vascular endothelial and smooth muscle cells but can be induced by exposure to progesterone. Although tightly regulated, induction of HLA-G expression in these cells may represent a promising and novel therapeutic strategy to protect against rejection and cardiac allograft vasculopathy after heart transplantation.

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Section: Discussionmentioning

confidence: 99%

“…Signaling molecules such as progesterone, 14,15 interferon-␥, 16 and interleukin-10, 17 which are present at high levels during gestation, are capable of enhancing HLA-G expression. Interventions associated with transplantation such as hypoxic injury 18 and immunosuppressive therapy 9 might also regulate this expression.…”

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confidence: 99%

Progesterone Induces Human Leukocyte Antigen-G Expression in Vascular Endothelial and Smooth Muscle Cells

et al. 2008

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“…A few HLA-G promoter binding factors and their target sites have been characterized such as CREB1 (28), IFN regulatory factor 1 (35), heat shock transcription factor 1 (36), or progesterone receptor (37). Microenvironmental parameters have been shown to play a key role in the modulation of HLA-G gene, including stress conditions such as heat shock (36) or hypoxia (38), cytokines such as IFN (35,39), IL-10 (40), leukemia inhibitory factor (41), GM-CSF (42), and hormones such as glucocorticoids (43) or progesterone (44).…”

Section: Rreb-1 Is a Transcriptionalmentioning

confidence: 99%

RREB-1 Is a Transcriptional Repressor of HLA-G

Flajollet

Poras

Carosella

et al. 2009

The Journal of Immunology

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The nonclassical HLA-G is a molecule specifically involved in immune tolerance with highly restricted tissue distribution in healthy conditions. Yet it is overexpressed in numerous tumors and in allografts with better acceptance. Major mechanisms involved in regulation of HLA-G transcription are still poorly described. Thus, to characterize these mechanisms we have developed a specific proteomic approach to identify proteins that bind differentially to the HLA-G gene promoter by promoter pull-down assay followed by spectrometry mass analysis. Among specific binding factors, we focused on RREB-1, a ras-responsive element binding protein 1. We demonstrated that RREB-1 represses HLA-G transcriptional activity and binds three ras response elements within the HLA-G promoter. RREB-1 protein, specifically in HLA-G-negative cells, interacts with subunits of CtBP complex implicated in chromatin remodeling. This demonstration is the first of a repressor factor of HLA-G transcriptional activity taking part in HLA-G repression by epigenetic mechanisms.

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“…In addition to cytokines, hormones like glucocorticoids (dexamethasone) and progesterone were shown to increase the secretion of both HLA-G5 and HLA-G6 by trophoblasts (Akhter et al, 2011;Moreau et al, 2001;Yie et al, 2006a;Yie et al, 2006b). HLA-G expression can be also influenced by Adenosine Triphosphate (ATP) and by the tryptophan catalayzing enzyme indoleamine 2 3-dioxygenase (IDO).…”

Section: Mechanisms Underlying Hla-g Expressionmentioning

confidence: 99%