Spatial targeting of the prostaglandin receptor EP2 is essential in driving a sustained PGE2-mediated cAMP signaling in the human endometrium
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ABSTRACT:
PROVIDER: PRJNA1033343 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26557468_1.fastq.gz | Fastqsanger.gz | |||
| SRR26557468_2.fastq.gz | Fastqsanger.gz | |||
| SRR26557469_1.fastq.gz | Fastqsanger.gz | |||
| SRR26557469_2.fastq.gz | Fastqsanger.gz | |||
| SRR26557470_1.fastq.gz | Fastqsanger.gz |
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Project description:In a process known as decidualization, progesterone signaling in the human endometrium converges with local cAMP production to drive morphometric and transcriptomic changes that prepare the endometrium for pregnancy. The source of cAMP has been contentious but the prostaglandin PGE2 signaling through EP2, its G-protein coupled receptor, remains a strong candidate. Cells often employ additional receptor regulation to diversify and prolong the cAMP signal and its down-steam effects, most notably through internalization and trafficking of receptors through endosomes. Here, we decidualized cultured endometrial stromal cells for 4-days with PGE2 and MPA (a progestin) and compared transcriptomic profiles with those depleted of either GIPC or APPL1, adaptor proteins involved in trafficking and recycling of EP2 respectively.
2024-10-27 | GSE246497 | GEO
Project description:While the role of prostaglandin E2 (PGE2) in promoting malignant progression is well-established, how to optimally block the activity of PGE2 signaling remains to be demonstrated. Clinical trials with prostaglandin pathway targeted agents have shown activity but without sufficient significance or dose-limiting toxicities that have prevented approval. PGE2 signals through four receptors (EP1-4) to modulate tumor progression. EP2 and EP4 signaling exacerbates tumor pathology and is immunosuppressive through potentiating cAMP production. EP1 and EP3 signaling has the opposite effect through increasing IP3 and decreasing cAMP. Using available small molecule antagonists of single EP receptors, the COX-2 inhibitor celecoxib, or a novel dual EP2/EP4 antagonist generated in this investigation, we tested which approach to block PGE2 signaling optimally restored immunologic activity in mouse and human immune cells and antitumor activity in syngeneic, spontaneous and xenograft tumor models. We found that dual antagonism of EP2 and EP4 together significantly enhanced the activation of PGE2-suppressed mouse and human monocytes and CD8+ T cells in vitro as compared to single EP antagonists. CD8+ T cell activation was dampened by single EP1 and EP3 antagonists. Dual EP2/EP4 PGE2 receptor antagonists increased TME lymphocyte infiltration and significantly reduced disease burden in multiple tumor models, including in the adenomatous polyposis coli (APC)min+/- spontaneous colorectal tumor model, compared to celecoxib. These results support a hypothesis that redundancy of EP2 and EP4 receptor signaling necessitates a therapeutic strategy of dual blockade of EP2 and EP4. Here we describe TPST-1495, a first-in-class orally available small molecule dual EP2/EP4 antagonist.
2023-08-21 | GSE229806 | GEO
Project description:Wild type tumor cells, producing high levels of prostaglandin E2 (MCG101, EP2 +/+), were inoculated on EP2 knockout (EP2 -/-) and EP2 wild type (EP2 +/+) mice. Solid tumors were dissected into tumor- and tumor-stroma tissue compartments for RNA expression microarray screening, followed by metabolic pathway analyses. The study aims to evaluate simultaneous gene pathway expressions in separate tissue compartments, such as isolated tumor tissue and tumor stroma respectively.
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Project description:IL-23 induces ptgs2 encoding cyclooxygenase 2 in Th17 cells and produces PGE2, which acts back on PGE2 receptors EP2 and EP4 in these cells and enhances IL-23-induced expression of an IL-23 receptor subunit gene, Il23r, by activating STAT3, CREB1 and NF-κB through cAMP-protein kinase A signaling. This PGE2 signaling also induces expression of various inflammation-related genes, which possibly function in Th17 cell-mediated pathology. Combined deletion of EP2 and EP4 selectively in T cells suppressed accumulation of IL-17A+ and IL-17A+IFN-γ+ pathogenic Th17 cells and abolished skin inflammation in IL-23-induced psoriasis mouse model. Analysis of human psoriatic skin biopsies shows positive correlation between PGE2 signaling and the IL-23/Th17 pathway.
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Project description:Microglia, the innate immune cells of the central nervous system, perform critical inflammatory and non-inflammatory functions to maintain homeostasis and normal neural function. However in Alzheimer’s disease (AD), these beneficial functions become progressively impaired, contributing to synapse and neuron loss and cognitive impairment. The inflammatory cyclooxygenase-PGE2 pathway, including the PGE2 receptor EP2, is implicated in AD development, both in human epidemiology and in transgenic models of AD. To test the transcriptional responses of EP2-deficient microglia to Aβ in vivo, we used mice in which the EP2 receptor is conditionally deleted in microglia using the CD11b-Cre transgene and floxed alleles of the EP2 gene. By injecting these mice with Aβ ICV and isolating microglia from the brains, we have been able to establish the transcriptional response of microglia to Aβ in vivo and test how EP2 deletion in microglia affects this response.
2015-02-20 | GSE57181 | GEO
Project description:Microglia, the innate immune cells of the central nervous system, perform critical inflammatory and non-inflammatory functions to maintain homeostasis and normal neural function. However in Alzheimer’s disease (AD), these beneficial functions become progressively impaired, contributing to synapse and neuron loss and cognitive impairment. The inflammatory cyclooxygenase-PGE2 pathway, including the PGE2 receptor EP2, is implicated in AD development, both in human epidemiology and in transgenic models of AD. To test the transcriptional responses of EP2-deficient microglia to Aβ in vivo, we used mice in which the EP2 receptor is conditionally deleted in microglia using the CD11b-Cre transgene and floxed alleles of the EP2 gene. By injecting these mice with Aβ ICV and isolating microglia from the brains, we have been able to establish the transcriptional response of microglia to Aβ in vivo and test how EP2 deletion in microglia affects this response. 8 month-old C57BL/6 mice, of the genotype CD11b-Cre; EP2+/+ or CD11b-Cre; EP2lox/lox, were injected I.C.V. with either Aβ or vehicle. 48 hours after injection, the mice were sacrificed and transcardially perfused with cold heparinized 0.9% NaCl. Brains were then removed from the mice and pooled, two brains of the same genotype per sample, to ensure adequate cell and RNA yield. The brains were then enzymatically dissociated for microglia isolation using the Neural Tissue Dissociation Kit (P), MACS Separation Columns (LS), and magnetic CD11b Microbeads from Miltenyi Biotec according to the manufacturer's protocol. Immediately after isolating the microglia, RNA was extracted from the cells for microarray analysis.
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Project description:MCG 101 tumors implanted on prostaglandin receptor EP2 wildtype and EP2 knockout mice
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Project description:The cervix represents a formidable structural barrier for successful induction of labor. Approximately 10% of pregnancies undergo induction of cervical ripening and labor with prostaglandin (PG) E2 or PGE analogs, often requiring many hours of hospitalization and monitoring. On the other, preterm cervical ripening in the second trimester predicts preterm birth. The regulatory mechanisms of this paradoxical function of the cervix are unknown. Here, we show that PGE2 utilizes cell-specific EP2 receptor-mediated increases in Ca2+ to dephosphorylate and translocate HDAC4 to the nucleus for repression of 15-hydroxy prostaglandin dehydrogenase (15-PGDH). The crucial role of 15-PGDH in cervical ripening was confirmed in vivo. Although PGE2 or PGDH inhibitor alone did not alter gestational length, treatment with PGDH inhibitor+PGE2 or metabolism-resistant dimethyl-PGE2 resulted in preterm cervical ripening and delivery in mice. The ability of PGE2 to selectively auto-amplify its own concentrations in stromal cells by signaling transcriptional repression of 15-PGDH elucidates long-sought-after molecular mechanisms that govern prostaglandin action in the cervix. This is the first report detailing unique mechanisms of action in the cervix and serves as a catalyst for (i) the use of PGDH inhibitors to initiate, or amplify low-dose PGE2-mediated cervical ripening, or (ii) EP2 receptor antagonists, HDAC4 inhibitors, and 15-PGDH activators to prevent preterm cervical ripening and preterm birth.
2017-07-07 | GSE99392 | GEO
Project description:Changes of genome-wide mRNA transcription levels of human ciliary smooth muscle (hCSM) cells were determined by treating hCSM cells in culture with 200 nM of either an prostaglandin E2 receptor subtype EP2 or subtype EP4 selective agonist for 6 hours in comparison to untreated controls. This was followed by competitive hybridization of fluorescent Cy3 or Cy5 labeled cRNA probes derived from the treated versus untreated control total RNA samples onto an Agilent Human Whole Genome Expression oligonucleotide microarray. Log 2 (LN) of the intra-slide ratios (RATIO, PRE_VALUE) of treated versus untreated samples was reported as VALUE in the sample files. Keywords: prostaglandin E2 receptor agonists, subtype EP2, subtype EP4, hCSM
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Project description:The discovery of immune checkpoint inhibitor (ICI) has highlighted the clinical importance of immune evasion in cancer. However, only a fraction of cancer patients show response to ICI, raising a question on immune suppression mechanisms other than immune checkpoint. In this study, we examined the role of the lipid inflammatory mediator PGE2 in immune evasion of the ICI-insensitive Lewis Lung Carcinoma line 1 (LLC1) mouse model. Inhibition of PGE receptors, EP2 and EP4, significantly suppressed tumor growth through the modulation of host immune cells. Single cell RNA-sequencing analysis revealed that EP2/4 inhibition elicited anti-tumor immunity through the reprogramming of inflammatory myeloid cells by downregulating expression of genes in NFB signaling and actions and suppression of the mregDC-regulatory T cell axis by downregulating genes associated with regulatory T cell recruitment and activation. Taken together, our work suggests that PGE2-EP2/EP4 signaling induces proinflammatory myeloid and tolerogenic lymphoid environments in ICI-insensitive tumors, which is amenable to EP2 and EP4 inhibitors..
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