EP4-Tg aortic VSMCs: Control vs PGE2
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA611821 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Microarray data of EP4-Tg VSMCs with or without 24 h of PGE2 (1 µmol/L)
2020-03-11 | GSE146758 | GEO
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..
2022-06-14 | GSE169688 | 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:ATAC sequencing was used to determine the impact of PGE2 signaling on NK cell function. Our analysis revealed that PGE2 induces a dysfunctional program in NK cells characterized by the inability to produce cytokines and chemokines upon their activation. Mechanistically, this program is governed by epigenetic changes downstream of the PGE2 receptors EP2 and EP4.
2024-09-04 | GSE249182 | GEO
Project description:RNA sequencing was used to determine the impact of PGE2 signaling on NK cell function. Our analysis revealed that PGE2 induces a dysfunctional program in NK cells characterized by the inability to produce cytokines and chemokines upon their activation. Mechanistically, this program is governed by transcriptional changes downstream of the PGE2 receptors EP2 and EP4.
2024-09-04 | GSE248977 | GEO
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.
2021-02-23 | GSE167248 | GEO
Project description:A persistent and non-resolving inflammatory response to accumulating Aβ peptide species is a cardinal feature in the development of Alzheimer's disease (AD). In response to accumulating Aβ peptide species, microglia, the innate immune cells of the brain, generate a toxic inflammatory response that accelerates synaptic and neuronal injury. Many pro-inflammatory signaling pathways are linked to progression of neurodegeneration. However, endogenous anti-inflammatory pathways capable of suppressing Aβ-induced inflammation represent a relatively unexplored area. Here we hypothesized that signaling through the prostaglandin-E2 (PGE2) EP4 receptor potently suppresses microglial inflammatory responses to Aβ42 peptides. In cultured microglial cells, EP4 stimulation attenuated levels of Aβ42-induced inflammatory factors and potentiated phagocytosis of Aβ42. Microarray analysis was performed and demonstrated that EP4 stimulation broadly opposed Aβ42-driven gene expression changes in microglia, with enrichment for targets of IRF1, IRF7, and NF-κB transcription factors.
2014-04-25 | GSE55627 | GEO
Project description:Prostaglandins (PGs) are inflammatory mediators. Aspirin-like non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX), an initiating enzyme of PG biosynthesis1. Daily use of aspirin-like drugs lowers the risk of cancer death not only prophylactically but therapeutically suggesting critical roles of PGs in cancer. However, general mechanisms by which PGs contribute to progression of a wide variety of human cancers remain elusive. Here, using scRNAseq analysis comparing immune cells infiltrating human tumors and a syngeneic mouse tumor, we have dissected this issue. We found that in human tumors, COX is dominantly expressed in infiltrating myeloid cells, and, among PG receptors, PGE receptor EP4 and to a less extent EP2 are expressed in both T cells and myeloid cells. DEG analysis between PTGER4hi and PTGER4lo CD8+ T cells indicates downregulation of IL-2-STAT5 signaling, oxidative phosphorylation, glycolysis and Myc targets in EP4hi CD8+ T cells, as revealed by suppressed expression of IL-2 receptor subunit gene and genes of OXPHOS, glycolytic enzymes and ribosomal proteins (RPs). Similar downregulation of OXPHOS, glycolytic enzymes and RP genes is found in PTGER4hi myeloid cells. Notably, such downregulation of OXPHOS and RP genes was found in immune cells infiltrating LLC1 mouse tumor, and reversed by treatment of tumor-bearing mice with EP2 and EP4 antagonists. In vitro in CD8+ T cells, EP4 is induced upon TCR activation and PGE2 acts on EP4, downregulates Il2ra expression and suppresses expression of Myc and PGC-1, thereby impairing both mitochondria and glycolysis as well as ribosome biogenesis in these cells. Similarly, EP4 is induced upon activation in macrophages and PGE2 downregulates Myc and OXPHOS pathwaysin these cells irrespective of other stimuli. These results demonstrate that PGE2 shapes immunosuppressive tumor microenvironment by hampering bioenergetic metabolism and ribosome biogenesis in infiltrating immune cells via EP4 receptor.
2024-09-28 | GSE242271 | GEO
Project description:Prostaglandins (PGs) are inflammatory mediators. Aspirin-like non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX), an initiating enzyme of PG biosynthesis1. Daily use of aspirin-like drugs lowers the risk of cancer death not only prophylactically but therapeutically suggesting critical roles of PGs in cancer. However, general mechanisms by which PGs contribute to progression of a wide variety of human cancers remain elusive. Here, using scRNAseq analysis comparing immune cells infiltrating human tumors and a syngeneic mouse tumor, we have dissected this issue. We found that in human tumors, COX is dominantly expressed in infiltrating myeloid cells, and, among PG receptors, PGE receptor EP4 and to a less extent EP2 are expressed in both T cells and myeloid cells. DEG analysis between PTGER4hi and PTGER4lo CD8+ T cells indicates downregulation of IL-2-STAT5 signaling, oxidative phosphorylation, glycolysis and Myc targets in EP4hi CD8+ T cells, as revealed by suppressed expression of IL-2 receptor subunit gene and genes of OXPHOS, glycolytic enzymes and ribosomal proteins (RPs). Similar downregulation of OXPHOS, glycolytic enzymes and RP genes is found in PTGER4hi myeloid cells. Notably, such downregulation of OXPHOS and RP genes was found in immune cells infiltrating LLC1 mouse tumor, and reversed by treatment of tumor-bearing mice with EP2 and EP4 antagonists. In vitro in CD8+ T cells, EP4 is induced upon TCR activation and PGE2 acts on EP4, downregulates Il2ra expression and suppresses expression of Myc and PGC-1, thereby impairing both mitochondria and glycolysis as well as ribosome biogenesis in these cells. Similarly, EP4 is induced upon activation in macrophages and PGE2 downregulates Myc and OXPHOS pathwaysin these cells irrespective of other stimuli. These results demonstrate that PGE2 shapes immunosuppressive tumor microenvironment by hampering bioenergetic metabolism and ribosome biogenesis in infiltrating immune cells via EP4 receptor.
2024-09-28 | GSE242272 | GEO
Project description:A persistent and non-resolving inflammatory response to accumulating A? peptide species is a cardinal feature in the development of Alzheimer's disease (AD). In response to accumulating A? peptide species, microglia, the innate immune cells of the brain, generate a toxic inflammatory response that accelerates synaptic and neuronal injury. Many pro-inflammatory signaling pathways are linked to progression of neurodegeneration. However, endogenous anti-inflammatory pathways capable of suppressing A?-induced inflammation represent a relatively unexplored area. Here we hypothesized that signaling through the prostaglandin-E2 (PGE2) EP4 receptor potently suppresses microglial inflammatory responses to A?42 peptides. In cultured microglial cells, EP4 stimulation attenuated levels of A?42-induced inflammatory factors and potentiated phagocytosis of A?42. Microarray analysis was performed and demonstrated that EP4 stimulation broadly opposed A?42-driven gene expression changes in microglia, with enrichment for targets of IRF1, IRF7, and NF-?B transcription factors. Primary microglia were isolated from the brains of postnatal day 7 C57BL/6J mouse pups using the Neural Tissue Dissociation Kit (P), MACS Separation Columns (LS), and magnetic CD11b Microbeads from Miltenyi Biotec (Auburn, CA). Microglia from three separate litters of pups were maintained as three independent biological replicates for each treatment. After being cultured for three days, microglia were treated with oligomeric A?42 (10uM) and/or the specific EP4 agonist AE1-329 (100nM) for 6 hours. These 4 treatment conditions (A? + AE1, A? alone, AE1 alone, and vehicle alone) and 3 independent biological replicates per treatment gave us 12 total samples. After 6 hours of treatment, RNA was isolated from the microglia for microarray analysis.
2014-04-25 | E-GEOD-55627 | biostudies-arrayexpress