E-Prostanoid-3 Receptors Mediate the Proinflammatory Actions of Prostaglandin E2 in Acute Cutaneous Inflammation

Goulet, Jennifer L.; Pace, Amy J.; Key, Mikelle L.; Byrum, Robert S.; Nguyen, Minh H.; Tilley, Stephen L.; Morham, Scott G.; Langenbach, Robert; Stock, Jeffrey L.; McNeish, John D.; Smithies, Oliver; Coffman, Thomas M.; Koller, Beverly H.

doi:10.4049/jimmunol.173.2.1321

Cited by 55 publications

(44 citation statements)

References 33 publications

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“…This conclusion derives from the results indicating that edema formation induced by PGE 2 injection is markedly prevented by the selective EP 3 L826266, but not the EP 2 AH6809 or EP 4 L161982 receptor antagonists. In fact, it has been recently demonstrated that edema formation and plasmatic extravasation induced by the topical application of arachidonic acid is found significantly decreased in mice with genic deletion of EP 3 receptors, whereas these responses remain unaffected in knockout mice for EP 1 , EP 2 , or EP 4 receptors (Goulet et al, 2004) In addition, Yuhki et al (2004) showed that IP, EP 2 , and EP 3 , but not EP 1 or EP 4 , receptor subtypes are largely implicated in exudate formation in the model of pleurisy induced by carrageenan in the mouse. Notably, we have also observed that the EP 3 receptor antagonist L826266 consistently inhibits carrageenan-induced edema in mice, to the same extent that it is able to reduce PGE 2 -mediated edema formation (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…by inflammatory mediators such as prostanoids (Goulet et al, 2004). Prostanoids consisting of the prostaglandins and thromboxanes are rapidly synthesized via the cyclooxygenase pathway in a variety of cells in response to various stimuli such as inflammation (Funk, 2001; for review, see Bos et al, 2004;Hata and Breyer, 2004).…”

Section: N-[(4r)-4-hydroxy-1-(1-methyl-1h-indol-3-yl)carbonyl-l-prolymentioning

confidence: 99%

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Pharmacological and Molecular Characterization of the Mechanisms Involved in Prostaglandin E₂-Induced Mouse Paw Edema

Claudino¹,

Kassuya²,

Ferreira³

et al. 2006

J Pharmacol Exp Ther

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The present study evaluated some of the mechanisms underlying prostaglandin E 2 (PGE 2 )-induced paw edema formation in mice. Intraplantar (i.pl.) injection of PGE 2 (0.10 -10.0 nmol/paw) into the hindpaw elicited a dose-related edema formation, with a mean ED 50 value of 0.42 nmol/paw. The coinjection of selec-L826266), but not EP 2 or EP 4 (all 10 nmol/paw), receptor antagonists significantly inhibited PGE 2 -induced paw edema. Like L826266, the PGE 2 -induced paw edema was markedly reduced by treatment with pertussis toxin and phospholipaseand the antagonist of vanilloid receptor (TRPV1) receptors 4Ј-chloro-3-methoxycinnamanilide (SB366791) (both 1 nmol/paw) also significantly inhibited PGE 2 -mediated paw edema. Conversely, the selective NK 2 , NK 3 , and calcitonin gene-related peptide (CGRP) CGRP 8-37 receptor antagonists all failed to interfere with PGE 2 -induced paw edema. The neonatal treatment of mice with capsaicin was also able to reduce PGE 2 -induced paw edema. The inhibitors of protein kinase C (PKC) 3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride (GF109203X) and mitogen protein-activated kinases (MAPKs; 30 nmol/paw) c-Jun NH 2 -terminal kinase (JNK) (anthra[1,9-cd]pyrazol-6(2H)-one; SP600125), extracellular signal-regulated kinase (PD98059), and p38 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; SB203580], but not protein kinase A, markedly decreased the PGE 2 -mediated edema formation. The i.pl. injection of PGE 2 (3 nmol/paw) induced a significant activation of MAPKs, namely, JNK and p38, an effect that was largely prevented by the selective EP 3 receptor antagonist L826266 (10 nmol/paw). Collectively, these findings indicate that edematogenic responses elicited by PGE 2 are mediated by EP 3 receptor activation, also involving the stimulation of PLC, PKC, and MAPKs pathways and the participation of TRPV1 and NK 1 receptors. These results make a considerable contribution to our comprehension of the mechanisms involved in PGE 2 -mediated inflammatory responses in mice.Inflammation is a complex physiological process that can be defined as a response to cellular and tissue injures caused by infections or physical and chemical stimuli. It is characterized by vasodilatation, increase of blood flow, and vascular permeability and cellular recruitment to the inflammatory site. These biochemical and cellular alterations are regulated This study was supported by grants

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Section: Discussionmentioning

confidence: 99%

Section: N-[(4r)-4-hydroxy-1-(1-methyl-1h-indol-3-yl)carbonyl-l-prolymentioning

confidence: 99%

Pharmacological and Molecular Characterization of the Mechanisms Involved in Prostaglandin E₂-Induced Mouse Paw Edema

Claudino¹,

Kassuya²,

Ferreira³

et al. 2006

J Pharmacol Exp Ther

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“…EP1 is coupled to intracellular Ca 2+ mobilization via G q , EP2 and EP4 are coupled to stimulation of adenylyl cyclase via G s , and EP3 is mainly coupled to inhibition of adenylyl cyclase via G i . Among the four PGE receptors, the EP3 receptor was proposed to participate in arachidonic acid (AA)-induced edema formation (10). These results suggest that PGE 2 may function as a link to an increase in vascular permeability and edema formation (11).…”

mentioning

confidence: 87%

Prostaglandin E2–EP3 Signaling Induces Inflammatory Swelling by Mast Cell Activation

Morimoto

Shirata

Taketomi

et al. 2014

The Journal of Immunology

123

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PGE2 has long been known as a potentiator of acute inflammation, but its mechanisms of action still remain to be defined. In this study, we employed inflammatory swelling induced in mice by arachidonate and PGE2 as models and dissected the role and mechanisms of action of each EP receptor at the molecular level. Arachidonate- or PGE2-induced vascular permeability was significantly reduced in EP3-deficient mice. Intriguingly, the PGE2-induced response was suppressed by histamine H1 antagonist treatment, histidine decarboxylase deficiency, and mast cell deficiency. The impaired PGE2-induced response in mast cell–deficient mice was rescued upon reconstitution with wild-type mast cells but not with EP3-deficient mast cells. Although the number of mast cells, protease activity, and histamine contents in ear tissues in EP3-deficient mice were comparable to those in wild-type mice, the histamine contents in ear tissues were attenuated upon PGE2 treatment in wild-type but not in EP3-deficient mice. Consistently, PGE2–EP3 signaling elicited histamine release in mouse peritoneal and bone marrow–derived mast cells, and it exerted degranulation and IL-6 production in a manner sensitive to pertussis toxin and a PI3K inhibitor and dependent on extracellular Ca2+ ions. These results demonstrate that PGE2 triggers mast cell activation via an EP3–Gi/o–Ca2+ influx/PI3K pathway, and this mechanism underlies PGE2-induced vascular permeability and consequent edema formation.

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“…Functionally, PGE 2 interacts with the four receptor subtypes (EP1-4). EP1 and EP3 primarily contribute to inflammatory responses, whereas EP4 promotes both cell survival and growth by activating antiapoptotic and proliferative cellular signaling pathways (Fujino et al, 2003;Hase et al, 2003;Hoshino et al, 2003;Goulet et al, 2004;Joseph et al, 2005). Moreover, EP4 is constitutively expressed in the colonic epithelium and further induced during IBD, along with PGE 2 (WiercinskaDrapalo et al, 1999;Northey et al, 2000;Takafuji et al, 2000;Nitta et al, 2002).…”

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confidence: 99%

The Prevention of Colitis by E Prostanoid Receptor 4 Agonist through Enhancement of Epithelium Survival and Regeneration

Jiang¹,

Nieves²,

Im³

et al. 2006

J Pharmacol Exp Ther

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Inflammatory bowel disease (IBD) is often triggered and/or exacerbated by nonsteroidal anti-inflammatory drugs (NSAIDs). Among various prostanoids affected by NSAIDs, prostaglandin E 2 (PGE 2 ), in particular, seems to play critical roles in IBD via the EP4 receptor, one of the four PGE 2 receptor subtypes (EP1-4). An EP4 agonist, [[3-[[(1R,2S,3R)(ONO-AE1-329), for example, when topically applied, has been reported to ameliorate typical colitis symptoms by suppressing the production of cytotoxic cytokines in the dextran sodium sulfate (DSS)-induced colitis model. EP4 agonists are also known, however, for their ability to protect epithelial cells from apoptosis in vitro, which may contribute to the protection of mucosal barrier functions. To investigate this potential application, we have tested another EP4-selective agonist in the DSS-indomethacin mouse colitis model. 7-[2-(3-Hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid methyl ester, C 23 H 33 NO 4 (AGN205203), an analog from the 8-azapiperidinone series of EP4 agonists, is metabolically and chemically more stable than the ONO agonist, because of its lack of oxidizable sulfur atoms in the ␣-chain and of 11-OH group, a potential source of ␤-elimination reaction. Treatment of mice subcutaneously with AGN205203 at 3 mg/kg/day minimized colitis symptoms, such as weight loss, diarrhea, and colonic bleeding. Further histological examination of colons revealed healthy surface columnar epithelial cells free of erosion and ulceration compared with those without the drug treatment. At cellular level, the drug treatment decreased colon epithelial apoptosis, prevented goblet cell depletion, and promoted epithelial regeneration. AGN205203 may be unique among known EP4 agonists for its metabolic and chemical stability, and it is amenable to systemic applications for the prevention and recovery of IBD.Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), affect approximately 1.4 million United States patients with 15,000 to 30,000 new cases annually at a mean age between 30s and early 40s. IBD patients suffer from body weight loss, diarrhea, fecal blood, and pain. Such symptoms could last for 15 to 25 years, frequently alternating between exacerbation and remission, thus severely affecting the quality of patient life and retarding the growth of young patients (Loftus, 2004;Isaacs et al., 2005). General consensus in the field is that IBD may arise from compromised colonic mucosal barrier functions that allow colonic antigens access to submucosal monocytes, which, upon activation, initiate innate immune responses and trigger cytotoxic cytokine production. Prevention and recovery of IBD thus largely depend on the integrity and maintenance of colonic mucosal barrier functions, which are compromised by inflammations along the entire bowel wall in CD and at the mucosal surface in UC.Current therapies primarily aim at the symptomatic remission by anti-inflammatory agents such as aminosalicylates and/or immunosuppres...

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E-Prostanoid-3 Receptors Mediate the Proinflammatory Actions of Prostaglandin E2 in Acute Cutaneous Inflammation

Cited by 55 publications

References 33 publications

Pharmacological and Molecular Characterization of the Mechanisms Involved in Prostaglandin E₂-Induced Mouse Paw Edema

Pharmacological and Molecular Characterization of the Mechanisms Involved in Prostaglandin E₂-Induced Mouse Paw Edema

Prostaglandin E2–EP3 Signaling Induces Inflammatory Swelling by Mast Cell Activation

The Prevention of Colitis by E Prostanoid Receptor 4 Agonist through Enhancement of Epithelium Survival and Regeneration

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E-Prostanoid-3 Receptors Mediate the Proinflammatory Actions of Prostaglandin E2 in Acute Cutaneous Inflammation

Cited by 55 publications

References 33 publications

Pharmacological and Molecular Characterization of the Mechanisms Involved in Prostaglandin E2-Induced Mouse Paw Edema

Pharmacological and Molecular Characterization of the Mechanisms Involved in Prostaglandin E2-Induced Mouse Paw Edema

Prostaglandin E2–EP3 Signaling Induces Inflammatory Swelling by Mast Cell Activation

The Prevention of Colitis by E Prostanoid Receptor 4 Agonist through Enhancement of Epithelium Survival and Regeneration

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Product

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Pharmacological and Molecular Characterization of the Mechanisms Involved in Prostaglandin E₂-Induced Mouse Paw Edema

Pharmacological and Molecular Characterization of the Mechanisms Involved in Prostaglandin E₂-Induced Mouse Paw Edema