15-Keto-PGE2 acts as a biased/partial agonist to terminate PGE2-evoked signaling

Prostaglandin E2 (PGE2) is well-known as an endogenous proinflammatory prostanoid synthesized from arachidonic acid by the activation of cyclooxygenase-2. E type prostanoid (EP) receptors are cognates for PGE2 that have four main subtypes: EP1 to EP4. Of these, the EP2 and EP4 prostanoid receptors have been shown to couple to Gαs-protein and can activate adenylyl cyclase to form cAMP. Studies suggest that EP4 receptors are involved in colorectal homeostasis and cancer development, but further work is needed to identify the roles of EP2 receptors in these functions. After sufficient inflammation has been evoked by PGE2, it is metabolized to 15-keto-PGE2. Thus, 15-keto-PGE2 has long been considered an inactive metabolite of PGE2. However, it may have an additional role as a biased and/or partial agonist capable of taking over the actions of PGE2 to gradually terminate reactions. Here, using cell-based experiments and in silico simulations, we show that PGE2-activated EP4 receptor–mediated signaling may evoke the primary initiating reaction of the cells, which would take over the 15-keto-PGE2–activated EP2 receptor–mediated signaling after PGE2 is metabolized to 15-keto-PGE2. The present results shed light on new aspects of 15-keto-PGE2, which may have important roles in passing on activities to EP2 receptors from PGE2-stimulated EP4 receptors as a “switched agonist.” This novel mechanism may be significant for gradually terminating PGE2-evoked inflammation and/or maintaining homeostasis of colorectal tissues/cells functions.

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The protective effects of 18β-glycyrrhetinic acid against inflammation microenvironment in gastric tumorigenesis targeting PGE2-EP2 receptor-mediated arachidonic acid pathway

European Journal of Inflammation ◽

10.1177/2058739218762993 ◽

2018 ◽

Vol 16 ◽

pp. 205873921876299 ◽

Cited By ~ 4

Author(s):

Donghui Cao ◽

Jing Jiang ◽

Dan Zhao ◽

Menghui Wu ◽

Houjun Zhang ◽

...

Keyword(s):

Arachidonic Acid ◽

Glycyrrhetinic Acid ◽

Prostaglandin E ◽

Protective Effects ◽

Cox 2 ◽

Anti Inflammatory ◽

Acid Pathway ◽

Ep2 Receptor ◽

Arachidonic Acid Pathway

Accumulating epidemiological and clinical evidence shows that inflammation is an important risk factor for gastrointestinal diseases. Glycyrrhiza glabra, a traditional Chinese medicine, has been shown to safely suppress gastric cancer; however, the anti-inflammatory mechanisms in gastric tumorigenesis have been poorly investigated. Therefore, this study is committed to demonstrate the in vivo anti-inflammatory effect of 18β-glycyrrhetinic acid (GRA), the main active component of G. glabra. The lymphocytes and macrophages were heavily infiltrated in the transgenic mice that highly expressed cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase (mPGES)-1; however, a significant reduction was observed after treatment with GRA. In addition, GRA downregulated the protein levels of COX-2, GαS, EP2, and β-catenin, which were involved in the arachidonic acid pathway. In conclusion, our study showed the potential protective effects of GRA against inflammatory environment that might be involved in gastric tumorigenesis in vivo through the PGE2-EP2 receptor-mediated arachidonic acid pathway.

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Luminal prostaglandin E receptors regulate salt and water transport in rabbit cortical collecting duct

AJP Renal Physiology ◽

10.1152/ajprenal.1995.269.2.f257 ◽

1995 ◽

Vol 269 (2) ◽

pp. F257-F265 ◽

Cited By ~ 22

Author(s):

Y. Sakairi ◽

H. R. Jacobson ◽

T. D. Noland ◽

M. D. Breyer

Keyword(s):

Collecting Duct ◽

Prostaglandin E ◽

Maximal Effect ◽

Dependent Manner ◽

Cortical Collecting Duct ◽

Dietary Salt ◽

Ep4 Receptor ◽

Osmotic Water ◽

Dietary Salt Restriction ◽

Ep2 Receptor

Prostaglandin E2 (PGE2) is the major renal cyclooxygenase metabolite of arachidonic acid. Urinary excretion of PGE2 is increased by dietary salt restriction, as well in cirrhosis and congestive heart failure. To determine whether urinary PGE2 affects transport along the nephron, the actions of luminal PGE2 were studied in the isolated perfused rabbit cortical collecting duct (CCD). Luminal PGE2 transiently hyperpolarized transepithelial voltage (Vt) in a dose-dependent manner (half-maximal effect approximately 10(-8) M) in contrast to a sustained depolarization of Vt produced by basolateral PGE2. Luminal PGE2 (0.1 microM) also significantly stimulated osmotic water permeability in the CCD. In CCDs cultured on semipermeable supports, apical PGE2 stimulated adenosine 3',5'-cyclic monophosphate (cAMP) production, suggesting the effects of luminal PGE2 are mediated by adenylyl cyclase-stimulating EP2 or EP4 receptors. Sulprostone, a PGE2 analogue selective for EP1 and EP3 receptors, affected Vt only when applied from the basolateral but not the luminal surface. Luminal application of the EP2 receptor agonist butaprost was also without effect. These results suggest that luminal PGE2 affects Vt via a butaprost-insensitive EP4 receptor. The Vt effect of luminal PGE2 was not blocked by pertussis toxin, also arguing against an EP3-mediated Gi-coupled effect. Finally, 1 microM luminal PGE2 only slightly increased CCD intracellular calcium concentration ([Ca2+]i), in contrast to the marked increase in [Ca2+]i produced by basolateral PGE2 (0.1 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

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Activation of prostaglandin EP4 receptor attenuates the induction of cyclooxygenase‐2 expression by EP2 receptor activation in human amnion fibroblasts: implications for parturition

The FASEB Journal ◽

10.1096/fj.201802642r ◽

2019 ◽

Vol 33 (7) ◽

pp. 8148-8160 ◽

Cited By ~ 6

Author(s):

Jiang-Wen Lu ◽

Wang-Sheng Wang ◽

Qiong Zhou ◽

Xiao-Wen Gan ◽

Leslie Myatt ◽

...

Keyword(s):

Receptor Activation ◽

Cyclooxygenase 2 ◽

Human Amnion ◽

Ep4 Receptor ◽

Ep2 Receptor

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Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.062053399 ◽

2002 ◽

Vol 99 (7) ◽

pp. 4580-4585 ◽

Cited By ~ 241

Author(s):

K. Yoshida ◽

H. Oida ◽

T. Kobayashi ◽

T. Maruyama ◽

M. Tanaka ◽

...

Keyword(s):

Bone Loss ◽

Bone Formation ◽

Receptor Activation ◽

Prostaglandin E ◽

Ep4 Receptor ◽

Prevention Of Bone Loss ◽

Stimulation Of

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Reduced glutathione modulates the arachidonic acid induced coronary reactions

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y84-211 ◽

1984 ◽

Vol 62 (10) ◽

pp. 1261-1267 ◽

Cited By ~ 2

Author(s):

Jaime Talesnik ◽

James N. Tsoporis

Keyword(s):

Arachidonic Acid ◽

Guinea Pig ◽

Reduced Glutathione ◽

Isolated Heart ◽

Prostaglandin E ◽

Guinea Pig Heart ◽

Rat Hearts ◽

Resistance Vessels ◽

Vasodilator Action ◽

Perfused Hearts

Coronary flow was recorded from spontaneously beating isolated perfused hearts of rats and guinea pigs. Arachidonic acid (AA), in single bolus doses, produced a fast short lasting coronary constriction followed by a slow developing but persisting vasodilation. These reactions (biphasic type) were characteristic of the guinea pig heart. In about 50% of the rat hearts the vasoconstrictor action predominated while the biphasic response was obtained in the rest of the experiments. Pretreatment of rats with aspirin prevented the responses to AA in the isolated heart. The administration of reduced glutathione (GSH) (about 1 mM to the rat or 0.5–0.75 mM to the guinea pig hearts) produced a marked development and (or) enhancement of the vasodilator action of AA. Repeated or single large doses of AA produced a change of pattern of responses from biphasic to constrictor type; the addition of GSH restored the vasodilator phase. Since GSH directs the endoperoxide metabolism towards the synthesis of prostaglandin E2 (PGE2), we postulate that the coronary dilatation of resistance vessels produced by AA would be due to a great extent to PGE2.

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Endogenous peroxidase in the nuclear envelope and endoplasmic reticulum of human monocytes in vitro: association with arachidonic acid metabolism

Blood ◽

10.1182/blood.v64.2.491.491 ◽

1984 ◽

Vol 64 (2) ◽

pp. 491-498 ◽

Cited By ~ 20

Author(s):

W Deimann ◽

M Seitz ◽

D Gemsa ◽

HD Fahimi

Keyword(s):

Endoplasmic Reticulum ◽

Protein Synthesis ◽

Arachidonic Acid ◽

Nuclear Envelope ◽

Culture Medium ◽

Acid Metabolism ◽

Arachidonic Acid Metabolism ◽

Substantial Decrease ◽

Prostaglandin E

Abstract he development of peroxidase (PO) reaction in the nuclear envelope (NE) and endoplasmic reticulum (ER) of monocytes differentiating in vitro and its relationship with arachidonic acid metabolism were studied. The PO, as visualized by the diaminobenzidine (DAB) technique, appeared in the NE and ER of the majority of monocytes within 24 hours of culture, with a substantial decrease thereafter. The influence of three major groups of agents--inhibitors of PO, of prostanoids, and of protein biosynthesis--upon the development of the PO reaction was examined. When aminotriazole, a PO inhibitor, was added to the culture medium, the appearance of PO was suppressed in the monocytes. The cyclooxygenase blocker, indomethacin, however, did not influence the development of PO. Also the blockers of protein synthesis, puromycin, cycloheximide, and actinomycin D, did not affect the appearance of PO. The prostanoids released from the monocytes, ie, prostaglandin E and thromboxane B2, were determined by radioimmunoassay and showed a time sequence of secretion that corresponded to the appearance of PO in the cells: a marked increase within the first 24 hours with a substantial decrease thereafter. The presence of the PO inhibitors aminotriazole and sodium azide in the culture medium produced a suppression of prostanoid release from the monocytes comparable with that of indomethacin. The data suggest that the PO in the NE and ER of differentiating monocytes in vitro (1) is associated with arachidonic acid metabolism, and (2) is not formed by de novo protein synthesis but rather by an activation process.

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PROSTAGLANDIN PRODUCTION BY INTRA-UTERINE TISSUES FROM PERIPARTURIENT SHEEP: USE OF A SUPERFUSION TECHNIQUE

Journal of Endocrinology ◽

10.1677/joe.0.0760111 ◽

1978 ◽

Vol 76 (1) ◽

pp. 111-121 ◽

Cited By ~ 82

Author(s):

M. D. MITCHELL ◽

A. P. F. FLINT

Keyword(s):

Arachidonic Acid ◽

Relative Rate ◽

Prostaglandin E ◽

Tissue Samples ◽

Prostaglandin Production ◽

Small Tissue ◽

Prostaglandin F

SUMMARY A technique for the continuous superfusion of small tissue samples in vitro has been applied to the study of prostaglandin production by ovine intra-uterine tissues. Basal and oxytocin-stimulated production of prostaglandins was studied at 120–125 days of pregnancy and after dexamethasone-induced delivery. In general, the relative rate of prostaglandin production by tissues was: foetal cotyledon = maternal cotyledon>myometrium and in quantitative order the prostaglandins produced were prostaglandin E (PGE) > prostaglandin F (PGF) = 13,14-dihydro-15-oxo-prostaglandin F (PGFM). Considerable variation was found between the rates of prostaglandin production in individual sheep. Oxytocin had no effect on the production of prostaglandins by tissues obtained before labour but myometrium and maternal cotyledon obtained at delivery exhibited a significant increase in production of PGE and PGF (though not PGFM) in response to oxytocin. Administration of arachidonic acid increased the production of PGE and PGF by the foetal cotyledon.

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Prostaglandin E2 mediates proliferation and chloride secretion in ADPKD cystic renal epithelia

AJP Renal Physiology ◽

10.1152/ajprenal.00010.2012 ◽

2012 ◽

Vol 303 (10) ◽

pp. F1425-F1434 ◽

Cited By ~ 17

Author(s):

Yu Liu ◽

Madhumitha Rajagopal ◽

Kim Lee ◽

Lorenzo Battini ◽

Daniel Flores ◽

...

Keyword(s):

Short Circuit ◽

Ussing Chamber ◽

Short Circuit Current ◽

Chloride Secretion ◽

Cell Number ◽

Flufenamic Acid ◽

Prostaglandin E ◽

Intracellular Camp ◽

Ep4 Receptor ◽

Autosomal Dominant Polycystic Kidney

Prostaglandin E2 (PGE2) contributes to cystogenesis in genetically nonorthologous models of autosomal dominant polycystic kidney disease (ADPKD). However, it remains unknown whether PGE2 induces the classic features of cystic epithelia in genetically orthologous models of ADPKD. We hypothesized that, in ADPKD epithelia, PGE2 induces proliferation and chloride (Cl−) secretion, two archetypal phenotypic features of ADPKD. To test this hypothesis, proliferation and Cl− secretion were measured in renal epithelial cells deficient in polycystin-1 (PC-1). PC-1-deficient cells increased in cell number (proliferated) faster than PC-1-replete cells, and this proliferative advantage was abrogated by cyclooxygenase inhibition, indicating a role for PGE2 in cell proliferation. Exogenous administration of PGE2 increased proliferation of PC-1-deficient cells by 38.8 ± 5.2% ( P < 0.05) but inhibited the growth of PC-1-replete control cells by 49.4 ± 1.9% ( P < 0.05). Next, we tested whether PGE2-specific E prostanoid (EP) receptor agonists induce intracellular cAMP and downstream β-catenin activation. PGE2 and EP4 receptor agonism (TCS 2510) increased intracellular cAMP concentration and the abundance of active β-catenin in PC-1-deficient cells, suggesting a mechanism for PGE2-mediated proliferation. Consistent with this hypothesis, antagonizing EP4 receptors reverted the growth advantage of PC-1-deficient cells, implicating a central role for the EP4 receptor in proliferation. To test whether PGE2-dependent Cl− secretion is also enhanced in PC-1-deficient cells, we used an Ussing chamber to measure short-circuit current ( Isc). Addition of PGE2 induced a fivefold higher increase in Isc in PC-1-deficient cells compared with PC-1-replete cells. This PGE2-induced increase in Isc in PC-1-deficient cells was blocked by CFTR-172 and flufenamic acid, indicating that PGE2 activates CFTR and calcium-activated Cl− channels. In conclusion, PGE2 activates aberrant signaling pathways in PC-1-deficient epithelia that contribute to the proliferative and secretory phenotype characteristic of ADPKD and suggests a therapeutic role for PGE2 inhibition and EP4 receptor antagonism.

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