PGE2 effect on unstimulated and exhausted human CD8+ T-cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE227316 | GEO | 2024/03/08
REPOSITORIES: GEO
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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:Prostaglandin E2 (PGE2) is involved in several inflammatory conditions including periodontitis. The aim of this study was to investigate the global gene expression profile of tumor necrosis factor alpha (TNFalpha) stimulated human gingival fibroblasts, focusing on signal pathways related to PGE2 production and the new PGE2-synthesizing enzymes, prostaglandin E synthases (PGES). The expression of microsomal prostaglandin E synthase-1 (mPGES-1) as well as the upstream cyclooxygenase-2 (COX-2) was up-regulated by TNFalpha, accompanied by increased PGE2 production. In contrast, the expression of microsomal prostaglandin E synthase-2 (mPGES-2) and cytosolic prostaglandin E synthase (cPGES) was unaffected by TNFalpha. Using microarray analysis in a time-course factorial design including time points 1, 3 and 6 h, we identified differentially expressed genes in response to TNFalpha treatment. Enrichment analysis of microarray data identified two positively regulated signal transduction pathways: c-Jun N-terminal kinase (JNK) and Nuclear Factor-kappaB (NF-kappaB). We used specific inhibitors and phosphorylation analysis to confirm their role in PGE2 regulation. Both JNK and NF-kappaB inhibitors reduced the TNFalpha-stimulated up-regulation of mPGES-1 and COX-2 as well as subsequent PGE2 production. The novel finding that TNFalpha-stimulated mPGES-1 is regulated by JNK suggests this kinase as a potential future target for treatment strategies in inflammatory disorders, including periodontitis. Keywords: Time course, gene expression, factorial design.
2008-12-11 | GSE13903 | GEO
Project description:These data show that the genes that distinguish myofibroblasts from fibroblasts are myriad, and that some genes not traditionally associated with myofibroblast differentiation may serve as novel therapeutic targets for fibrosing disorders. Gene expression levels were assessed from total RNA on the Affymetrix U219 microarray. Here, we use transforming growth factor-β1 (TGF-β1) and prostaglandin E2 (PGE2), which has recently been shown to reverse myofibroblast differentiation, to investigate the transcriptomic changes that occur during TGF-β1-induced differentiation and PGE2-induced de-differentiation of myofibroblasts.
2015-06-30 | E-GEOD-63659 | biostudies-arrayexpress
Project description:Prostaglandin E2 (PGE2) is involved in several inflammatory conditions including periodontitis. The aim of this study was to investigate the global gene expression profile of tumor necrosis factor alpha (TNFalpha) stimulated human gingival fibroblasts, focusing on signal pathways related to PGE2 production and the new PGE2-synthesizing enzymes, prostaglandin E synthases (PGES). The expression of microsomal prostaglandin E synthase-1 (mPGES-1) as well as the upstream cyclooxygenase-2 (COX-2) was up-regulated by TNFalpha, accompanied by increased PGE2 production. In contrast, the expression of microsomal prostaglandin E synthase-2 (mPGES-2) and cytosolic prostaglandin E synthase (cPGES) was unaffected by TNFalpha. Using microarray analysis in a time-course factorial design including time points 1, 3 and 6 h, we identified differentially expressed genes in response to TNFalpha treatment. Enrichment analysis of microarray data identified two positively regulated signal transduction pathways: c-Jun N-terminal kinase (JNK) and Nuclear Factor-kappaB (NF-kappaB). We used specific inhibitors and phosphorylation analysis to confirm their role in PGE2 regulation. Both JNK and NF-kappaB inhibitors reduced the TNFalpha-stimulated up-regulation of mPGES-1 and COX-2 as well as subsequent PGE2 production. The novel finding that TNFalpha-stimulated mPGES-1 is regulated by JNK suggests this kinase as a potential future target for treatment strategies in inflammatory disorders, including periodontitis. Keywords: Time course, gene expression, factorial design. Three human gingival fibroblast cell lines were established from gingival biopsies obtained from 3 healthy patients, 3 to 12 years of age, with no clinical signs of periodontal disease. Cells were incubated with or without TNF-alpha (20 ng/ml) for 1, 3 or 6h. After incubation for 1, 3 or 6 h in the two conditions, the cells were immediately frozen in liquid nitrogen and then stored at -70°C for subsequent isolation of total RNA. The experimental design of the microarray study was set up as a time-course factorial design, to best observe the TNF-alpha induced gene expression changes over time. C++ program (G.F. Glonek, P.J. Solomon, Factorial and time course designs for cDNA microarray experiments, Biostatistics 5 (2004) 89-111) was used to determine the exact layout of the design in order to estimate the interaction effect between treatment and time, i.e. genes that are differentially expressed over time, with optimal statistical efficiency. Cyanine 5 and cyanine 3 were used for labeling. For each cell line 12 hybridizations were performed in a time-course factorial design. In total, 36 hybridizations were performed.
2008-12-10 | E-GEOD-13903 | biostudies-arrayexpress
Project description:Metabolic engagement is intrinsic to immune cell function. Prostaglandin E2 (PGE2) has been shown to modulate macrophage activation, yet how PGE2 might affect metabolism is unclear. Here we show that PGE2 causes mitochondrial membrane potential (Δψm) to dissipate in interleukin-4 activated macrophages (M(IL-4)). Effects on Δψm are a consequence of PGE2-initiated transcriptional regulation of genes in the malate-aspartate shuttle (MAS), particularly GOT1. Reduced Δψm causes alterations in the expression of 126 voltage regulated genes (VRGs) including Resistin like molecule-α (RELMα), a key marker of M(IL-4), and genes that regulate cell cycle, The transcription factor ETS variant 1 (ETV1) plays a role in the regulation of 38% of the VRGs. These results reveal ETV1 as a Δψm-sensitive transcription factor, and Δψm as a mediator of mitochondrial-directed nuclear gene expression.
2021-09-08 | PXD010997 | Pride
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:Prostaglandin E2 (PGE2) Enhances Aged Hematopoietic Stem Cell Function
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Project description:Fresh human breast tumor tissue was dissociated into single cells and viably frozen. Patient samples were annotated as having an ""exhausted"" or ""non-exhausted"" immune environment based on CyTOF characterization of T cell phenotypes (Wagner et al, Cell 2019). 14 samples (7 exhausted, 7 non-exhausted) were selected for scRNA-seq (without prior cell type enrichment) with the goal to compare the two immune environment types and to comprehensively characterize exhaustion-associated features of the tumor microenvironment.
2023-08-25 | E-MTAB-10607 | biostudies-arrayexpress
Project description:Metabolic engagement is intrinsic to immune cell function. Prostaglandin E2 (PGE2) has been shown to modulate macrophage activation, yet how PGE2 might affect metabolism is unclear. Here we show that PGE2 causes mitochondrial membrane potential (Δψm) to dissipate in interleukin-4 activated macrophages (M(IL-4)). Effects on Δψm are a consequence of PGE2-initiated transcriptional regulation of genes in the malate-aspartate shuttle (MAS), particularly GOT1. Reduced Δψm causes alterations in the expression of 126 voltage regulated genes (VRGs) including Resistin like molecule-α (RELMα), a key marker of M(IL-4), and genes that regulate cell cycle. The transcription factor ETS variant 1 (ETV1) plays a role in the regulation of 38% of the VRGs. These results reveal ETV1 as a Δψm-sensitive transcription factor, and Δψm as a mediator of mitochondrial-directed nuclear gene expression.
2019-01-16 | GSE119463 | GEO
Project description:Metabolic engagement is intrinsic to immune cell function. Prostaglandin E2 (PGE2) has been shown to modulate macrophage activation, yet how PGE2 might affect metabolism is unclear. Here we show that PGE2 causes mitochondrial membrane potential (Δψm) to dissipate in interleukin-4 activated macrophages (M(IL-4)). Effects on Δψm are a consequence of PGE2-initiated transcriptional regulation of genes in the malate-aspartate shuttle (MAS), particularly GOT1. Reduced Δψm causes alterations in the expression of 126 voltage regulated genes (VRGs) including Resistin like molecule-α (RELMα), a key marker of M(IL-4), and genes that regulate cell cycle. The transcription factor ETS variant 1 (ETV1) plays a role in the regulation of 38% of the VRGs. These results reveal ETV1 as a Δψm-sensitive transcription factor, and Δψm as a mediator of mitochondrial-directed nuclear gene expression.
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