EP4 receptor stimulation down-regulates human eosinophil function

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Abstract

Accumulation of eosinophils in tissue is a hallmark of allergic inflammation. Here we observed that a selective agonist of the PGE ₂ receptor EP4, ONO AE1-329, potently attenuated the chemotaxis of human peripheral blood eosinophils, upregulation of the adhesion molecule CD11b and the production of reactive oxygen species. These effects were accompanied by the inhibition of cytoskeletal rearrangement and Ca ²⁺ mobilization. The involvement of the EP4 receptor was substantiated by a selective EP4 antagonist, which reversed the inhibitory effects of PGE ₂ and the EP4 agonist. Selective kinase inhibitors revealed that the inhibitory effect of EP4 stimulation on eosinophil migration depended upon activation of PI 3-kinase and PKC, but not cAMP. Finally, we found that EP4 receptors are expressed by human eosinophils, and are also present on infiltrating leukocytes in inflamed human nasal mucosa. These data indicate that EP4 agonists might be a novel therapeutic option in eosinophilic diseases.

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Most cited references 59

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Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial.

Ruth H Green, Christopher E. Brightling, Susan Mckenna … (2002)

Treatment decisions in asthma are based on assessments of symptoms and simple measures of lung function, which do not relate closely to underlying eosinophilic airway inflammation. We aimed to assess whether a management strategy that minimises eosinophilic inflammation reduces asthma exacerbations compared with a standard management strategy. We recruited 74 patients with moderate to severe asthma from hospital clinics and randomly allocated them to management either by standard British Thoracic Society asthma guidelines (BTS management group) or by normalisation of the induced sputum eosinophil count and reduction of symptoms (sputum management group). We assessed patients nine times over 12 months. The results were used to manage those in the sputum management group, but were not disclosed in the BTS group. The primary outcomes were the number of severe exacerbations and control of eosinophilic inflammation, measured by induced sputum eosinophil count. Analyses were by intention to treat. The sputum eosinophil count was 63% (95% CI 24-100) lower over 12 months in the sputum management group than in the BTS management group (p=0.002). Patients in the sputum management group had significantly fewer severe asthma exacerbations than did patients in the BTS management group (35 vs 109; p=0.01) and significantly fewer patients were admitted to hospital with asthma (one vs six, p=0.047). The average daily dose of inhaled or oral corticosteroids did not differ between the two groups. A treatment strategy directed at normalisation of the induced sputum eosinophil count reduces asthma exacerbations and admissions without the need for additional anti-inflammatory treatment.

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Eosinophilic inflammation in asthma.

J Bousquet, P Chanez, J Y Lacoste … (1990)

The importance of eosinophils in the pathogenesis of bronchial asthma is not established. In an attempt to evaluate the role of eosinophilic inflammation in asthma, we compared 10 normal subjects with 43 patients with chronic asthma, 19 of whom had severe disease as assessed by a clinical scoring method described by Aas and by pulmonary-function tests. Eosinophils were counted in peripheral blood and bronchoalveolar-lavage fluid, and in biopsy specimens obtained from the patients and post mortem from 8 subjects without asthma, but not from the 10 normal controls. Eosinophil cationic protein was titrated by radioimmunoassay in the bronchoalveolar-lavage fluid from all subjects and studied by immunohistochemistry in the biopsy specimens. There was a significant increase in the number of peripheral-blood eosinophils in the patients that was correlated with the clinical severity of asthma (P less than 0.001) and pulmonary function (P less than 0.03). Levels of eosinophils and eosinophil cationic protein were increased in the bronchoalveolar-lavage fluid from the patients and were also correlated with the severity of asthma (P less than 0.001 and P less than 0.002, respectively). Hematoxylin-eosin staining of bronchial-biopsy specimens showed that intraepithelial eosinophils were present only in patients with asthma. Immunohistochemical analysis of eosinophil cationic protein revealed that normal subjects had only a few nondegranulated eosinophils deep in the submucosa, whereas all the patients had degranulated eosinophils beneath the basement membrane and among epithelial cells. In some patients there was a relation between the presence of degranulated eosinophils and epithelial damage. Eosinophilic inflammation of the airways is correlated with the severity of asthma. These cells are likely to play a part in the epithelial damage seen in this disease.

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Prostaglandin E2 induced functional expression of early growth response factor-1 by EP4, but not EP2, prostanoid receptors via the phosphatidylinositol 3-kinase and extracellular signal-regulated kinases.

Wei Xu, W Regan, Hiromichi Fujino (2003)

Prostaglandin E(2) (PGE(2)) mediates its physiological effects by interactions with a subfamily of G-protein-coupled receptors known as EP receptors. These receptors consist of four primary subtypes named EP(1), EP(2), EP(3), and EP(4). The EP(2) and EP(4) subtypes are known to couple to Galpha(s) and stimulate intracellular cyclic 3,5- adenosine monophosphate formation, whereas the EP(1) and EP(3) receptors are known to couple to Galpha(q) and Galpha(i), respectively. Recently we found that EP(2) and EP(4) receptors can activate T-cell factor signaling; however, EP(2) receptors did this primarily through a cAMP-dependent protein kinase-dependent pathway, whereas EP(4) receptors primarily utilized a phosphatidylinositol 3-kinase (PI3K)-dependent pathway (Fujino, H., West, K. A., and Regan, J. W. (2002) J. Biol. Chem. 277, 2614-2619). We now report that PGE(2) stimulation of EP(4) receptors, but not EP(2) receptors, leads to phosphorylation of the extracellular signal-regulated kinases (ERKs) through a PI3K-dependent mechanism. Furthermore, this activation of PI3K/ERK signaling by the EP(4) receptors induces the functional expression of early growth response factor-1 (EGR-1). Under the same conditions induction of EGR-1 protein expression was not observed following PGE(2) stimulation of EP(2) receptors. These findings point to important differences in the signaling potential of the EP(2) and EP(4) receptors, which could be significant with respect to the potential involvement of EP(4) receptors in inflammation and cancer.

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Author and article information

Contributors

: +43-316-3804508 , +43-316-3809645 , akos.heinemann@medunigraz.at

Journal

Journal ID (nlm-ta): Cell Mol Life Sci

Title: Cellular and Molecular Life Sciences

Publisher: SP Birkhäuser Verlag Basel (Basel )

ISSN (Print): 1420-682X

ISSN (Electronic): 1420-9071

Publication date (Electronic): 2 March 2011

Publication date PMC-release: 2 March 2011

Publication date (Print): November 2011

Volume: 68

Issue: 21

Pages: 3573-3587

Affiliations

[1 ]Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4, 8010 Graz, Austria

[2 ]Center for Medical Research, Medical University of Graz, Graz, Austria

[3 ]Department of Otorhinolaryngology, Medical University of Graz, Graz, Austria

[4 ]Institute of Pathology, Medical University of Graz, Graz, Austria

Article

Publisher ID: 642

DOI: 10.1007/s00018-011-0642-5

PMC ID: 3192285

PubMed ID: 21365278

SO-VID: 239059ca-3804-41e2-9ab3-956df040e82f

History

Date received : 3 May 2010

Date revision received : 7 February 2011

Date accepted : 15 February 2011

Custom metadata

ScienceOpen disciplines: Molecular biology

Keywords: receptors,eosinophils,prostaglandins,reactive oxygen species,degranulation,chemotaxis

Data availability:

ScienceOpen disciplines: Molecular biology

Keywords: receptors, eosinophils, prostaglandins, reactive oxygen species, degranulation, chemotaxis

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