The pharmacological effect of BGC20-1531, a novel prostanoid EP4 receptor antagonist, in the prostaglandin E2 human model of headache.
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ABSTRACT:
SUBMITTER: Antonova M
PROVIDER: S-EPMC3173651 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND: Mast cells play a critical role in allergic and inflammatory diseases, including exercise-induced bronchoconstriction (EIB) in asthma. The mechanism underlying EIB is probably related to increased airway fluid osmolarity that activates mast cells to the release inflammatory mediators. These mediators then act on bronchial smooth muscle to cause bronchoconstriction. In parallel, protective substances such as prostaglandin E2 (PGE2) are probably also released and could explain the refractory period observed in patients with EIB. OBJECTIVE: This study aimed to evaluate the protective effect of PGE2 on osmotically activated mast cells, as a model of exercise-induced bronchoconstriction. METHODS: We used LAD2, HMC-1, CD34-positive, and human lung mast cell lines. Cells underwent a mannitol challenge, and the effects of PGE2 and prostanoid receptor (EP) antagonists for EP(1-4) were assayed on the activated mast cells. Beta-hexosaminidase release, protein phosphorylation, and calcium mobilization were assessed. RESULTS: Mannitol both induced mast cell degranulation and activated phosphatidyl inositide 3-kinase and mitogen-activated protein kinase (MAPK) pathways, thereby causing de novo eicosanoid and cytokine synthesis. The addition of PGE2 significantly reduced mannitol-induced degranulation through EP(2) and EP(4) receptors, as measured by beta-hexosaminidase release, and consequently calcium influx. Extracellular-signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 phosphorylation were diminished when compared with mannitol activation alone. CONCLUSIONS: Our data show a protective role for the PGE2 receptors EP(2) and EP(4) following osmotic changes, through the reduction of human mast cell activity caused by calcium influx impairment and MAP kinase inhibition.
| S-EPMC4203853 | biostudies-literature
Project description:Safety, tolerability, and pharmacology profiles of LY3127760, an EP4 antagonist, were explored in healthy subjects in a subject/investigator-blind, parallel-group, multiple-ascending dose study. Cohorts consisted of 13 patients randomized to LY3127760, celecoxib (400 mg), or placebo (9:2:2 ratio) for 28 days. LY3127760 was well tolerated; the most commonly observed adverse events were gastrointestinal, similar to celecoxib. LY3127760 increased release of ex vivo tumor necrosis factor alpha after lipopolysaccharide/prostaglandin E2 stimulation when compared with placebo, suggesting a dose-dependent blockade of the EP4 receptor. Compared with placebo, 24-h urinary excretion of prostaglandin E metabolite was modestly increased; prostacyclin metabolite was inhibited; and thromboxane A2 metabolite was unchanged. Effects on sodium and potassium excretion were similar to those of celecoxib. We conclude that LY3127760 demonstrated similar effects on prostacyclin synthesis and renal sodium retention as celecoxib. These data support exploration of LY3127760 at daily doses of 60 mg to 600 mg in phase II trials. This trial's registration number: NCT01968070.
| S-EPMC5759725 | biostudies-literature
Project description:Increased expression of several subtypes of prostaglandin E(2) receptors (EP1-4) has recently been described in clinical and experimental myocardial ischaemia/reperfusion (I/R) injury. However, their pathophysiological significance in I/R remains obscure. Thus, we determined whether the activation of the prostanoid receptor, EP4, suppresses myocardial I/R injury.To analyse the role of EP4, we administered an EP4 selective agonist (EP4RAG, 1 or 3 mg/kg) or vehicle to rats with myocardial I/R injury. After 7 days of reperfusion, I/R rats exhibited left ventricular (LV) dilatation and contractile dysfunction with myocyte hypertrophy and interstitial fibrosis. EP4RAG significantly reduced infarction area/ischaemic myocardium (72.4 +/- 0.7 vs. 23.3 +/- 0.6%; P < 0.05) and improved LV contraction and dilatation compared with that of the vehicle. EP4RAG also attenuated the recruitment of inflammatory cells, especially macrophages, and interstitial fibrosis in hearts. Monocyte chemoattractant protein (MCP)-1 and other cytokines were increased in both non-ischaemic (area not at risk, ANAR) and ischaemic (area at risk, AAR) myocardium; however, western blot analysis and RNase protection assay showed that EP4RAG suppressed these changes. Gelatin zymography revealed EP4RAG significantly reduced matrix metalloproteinase-2 and -9 activities in both ANAR and AAR. Chemoattractant assay demonstrated that EP4RAG suppressed the migration of cytokine-stimulated macrophages and decreased the level of MCP-1 production in the supernatant (587.3 +/- 55.3 vs. 171.5 +/- 47.5 pg/mL; P < 0.05).The data suggest that the EP4 agonist is effective for attenuation of I/R injury by suppressing MCP-1 and the infiltration of inflammatory cells, especially macrophages.
| S-EPMC2721641 | biostudies-literature
Project description:Pancreatic stellate cells are source of dense fibrotic stroma, a constant pathological feature of chronic pancreatitis and pancreatic adenocarcinoma. We observed correlation between levels of cyclooxygenase 2 (COX-2) and its product prostaglandin E2 (PGE2) and the extent of pancreatic fibrosis. The aims of this study were to delineate the effects of PGE2 on immortalized human pancreatic stellate cells (HPSCs) and to identify the receptor involved.Immunohistochemistry, reverse transcription-polymerase chain reaction and quantitative reverse transcription-polymerase chain reaction were used to assess COX-2, extracellular matrix, and matrix metalloproteinase gene expression. Eicosanoid profile was determined by liquid chromatography-tandem mass spectrometry. Human pancreatic stellate cell proliferation was assessed by MTS assay, migration by Boyden chamber assay, and invasion using an invasion chamber. Transient silencing was obtained by small interfering RNA.Human pancreatic stellate cells express COX-2 and synthesize PGE2. Prostaglandin E2 stimulated HPSC proliferation, migration, and invasion and stimulated expression of both extracellular matrix and matrix metalloproteinase genes. Human pancreatic stellate cells expressed all 4 EP receptors. Only blocking the EP4 receptor resulted in abrogation of PGE2-mediated HPSC activation. Specificity of EP4 for the effects of PGE2 on stellate cells was confirmed using specific antagonists.Our data indicate that PGE2 regulates pancreatic stellate cell profibrotic activities via EP4 receptor, thus suggesting EP4 receptor as useful therapeutic target for pancreatic cancer to reduce desmoplasia.
| S-EPMC3600062 | biostudies-literature
Project description:UV radiation induces systemic immunosuppression. Because nonsteroidal anti-inflammatory drugs suppress UV-induced immunosuppression, prostanoids have been suspected as a crucial mediator of this UV effect. However, the identity of the prostanoid involved and its mechanism of action remain unclear. Here, we addressed this issue by subjecting mice deficient in each prostanoid receptor individually or mice treated with a subtype-specific antagonist to UV irradiation. Mice treated with an antagonist for prostaglandin E receptor subtype 4 (EP4), but not those deficient in other prostanoid receptors, show impaired UV-induced immunosuppression, whereas administration of an EP4 agonist rescues the impairment of the UV-induced immunosuppression in indomethacin-treated mice. The EP4 antagonist treatment suppresses an increase in the number of CD4(+)/forkhead box P3-positive (Foxp3(+)) regulatory T cells (Treg cells) in the peripheral lymph nodes (LNs) and dendritic cells expressing DEC205 in the LNs and the skin after UV irradiation. Furthermore, the EP4 antagonist treatment down-regulates UV-induced expression of receptor activator of NF-?B ligand (RANKL) in skin keratinocytes. Finally, administration of anti-RANKL antibody abolishes the restoration of UV-induced immunosuppression by EP4 agonism in indomethacin-treated mice. Thus, prostaglandin E(2) (PGE(2))-EP4 signaling mediates UV-induced immunosuppression by elevating the number of Treg cells through regulation of RANKL expression in the epidermis.
| S-EPMC3081002 | biostudies-literature
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: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
Project description:A persistent and nonresolving 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 proinflammatory 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 report 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 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. In vivo, conditional deletion of microglial EP4 in APPSwe-PS1?E9 (APP-PS1) mice conversely increased inflammatory gene expression, oxidative protein modification, and A? deposition in brain at early stages of pathology, but not at later stages, suggesting an early anti-inflammatory function of microglial EP4 signaling in the APP-PS1 model. Finally, EP4 receptor levels decreased significantly in human cortex with progression from normal to AD states, suggesting that early loss of this beneficial signaling system in preclinical AD development may contribute to subsequent progression of pathology.
| S-EPMC3996215 | biostudies-literature
Project description:With increasing body weight, macrophages accumulate in adipose tissue. There, activated macrophages secrete numerous proinflammatory cytokines and chemokines, giving rise to chronic inflammation and insulin resistance. Prostaglandin E2 suppresses macrophage activation via EP4; however, the role of EP4 signaling in insulin resistance and type 2 diabetes mellitus remains unknown. In this study, we treated db/db mice with an EP4-selective agonist, ONO-AE1-329, for 4 weeks to explore the role of EP4 signaling in obesity-related inflammation in vivo. Administration of the EP4 agonist did not affect body weight gain or food intake; however, in the EP4 agonist-treated group, glucose tolerance and insulin resistance were significantly improved over that of the vehicle-treated group. Additionally, administration of the EP4 agonist inhibited the accumulation of F4/80-positive macrophages and the formation of crown-like structures in white adipose tissue, and the adipocytes were significantly smaller. The treatment of the EP4 agonist increased the number of anti-inflammatory M2 macrophages, and in the stromal vascular fraction of white adipose tissue, which includes macrophages, it markedly decreased the levels of proinflammatory cytokines and chemokines. Further, EP4 activation increased the expression of adiponectin and peroxidase proliferator-activated receptors in white adipose tissue. Next, we examined in vitro M1/M2 polarization assay to investigate the impact of EP4 signaling on determining the functional phenotypes of macrophages. Treatment with EP4 agonist enhanced M2 polarization in wild-type peritoneal macrophages, whereas EP4-deficient macrophages were less susceptible to M2 polarization. Notably, antagonizing peroxidase proliferator-activated receptor ? activity suppressed EP4 signaling-mediated shift toward M2 macrophage polarization. Thus, our results demonstrate that EP4 signaling plays a critical role in obesity-related adipose tissue inflammation and insulin resistance by regulating macrophage recruitment and polarization. The activation of EP4 signaling holds promise for treating obesity and type 2 diabetes mellitus.
| S-EPMC4550358 | biostudies-literature
Project description:Accumulating evidence indicates that elevated levels of prostaglandin E(2) (PGE(2)) can increase intestinal epithelial cell proliferation, and thus play a role in colorectal tumorigenesis. PGE(2) exerts its effects through four G-protein-coupled PGE receptor (EP) subtypes, named the EP1, EP2, EP3, and EP4. Increased phosphorylation of extracellular regulated kinases (ERK1/2) is required for PGE(2) to stimulate cell proliferation of human colon cancer cells. However, the EP receptor(s) that are involved in this process remain unknown. We provide evidence that L-161,982, a selective EP4 receptor antagonist, completely blocks PGE(2)-induced ERK phosphorylation and cell proliferation of HCA-7 cells. In order to identify downstream target genes of ERK1/2 signaling, we found that PGE(2) induces expression of early growth response gene-1 (EGR-1) downstream of ERK1/2 and regulates its expression at the level of transcription. PGE(2) treatment induces phosphorylation of cyclic AMP response element binding protein (CREB) at Ser133 residue and CRE-mediated luciferase activity in HCA-7 cells. Studies with dominant-negative CREB mutant (ACREB) provide clear evidence for the involvement of CREB in PGE(2) driven egr-1 transcription in HCA-7 cells. In conclusion, this study reveals that egr-1 is a target gene of PGE(2) in HCA-7 cells and is regulated via the newly identified EP4/ERK/CREB pathway. Finally our results support the notion that antagonizing EP4 receptors may provide a novel therapeutic approach to the treatment of colon cancer.
| S-EPMC2706013 | biostudies-literature