D-type prostanoid receptor enhances the signaling of chemoattractant receptor–homologous molecule expressed on TH2 cells

Sedej, Miriam; Schröder, R; Bell, Kathrin; Platzer, Wolfgang; Vukoja, Anela; Kostenis, Evi; Heinemann, Ákos; Waldhoer, Maria

doi:10.1016/j.jaci.2011.08.015

Cited by 23 publications

(39 citation statements)

References 49 publications

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“…Agonist-mediated intracellular Ca 21 release was measured in a 96-well plate format (FlexStation II; Molecular Devices, Sunnyvale, CA), as previously described (Sedej et al, 2012 …”

Section: Intracellular Ca 21 Release Assaysmentioning

confidence: 99%

A Selective Antagonist Reveals a Potential Role of G Protein–Coupled Receptor 55 in Platelet and Endothelial Cell Function

Kargl

Brown

Andersen

et al. 2013

J Pharmacol Exp Ther

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The G protein-coupled receptor 55 (GPR55) is a lysophosphatidylinositol (LPI) receptor that is also responsive to certain cannabinoids. Although GPR55 has been implicated in several (patho)physiologic functions, its role remains enigmatic owing mainly to the lack of selective GPR55 antagonists. Here we show that the compound CID16020046 ((4-[4-(3-In yeast cells expressing human GPR55, CID16020046 antagonized agonistinduced receptor activation. In human embryonic kidney (HEK293) cells stably expressing human GPR55, the compound behaved as an antagonist on LPI-mediated Ca 21 release and extracellular signal-regulated kinases activation, but not in HEK293 cells expressing cannabinoid receptor 1 or 2 (CB 1 or CB 2 ). CID16020046 concentration dependently inhibited LPI-induced activation of nuclear factor of activated T-cells (NFAT), nuclear factor k of activated B cells (NF-kB) and serum response element, translocation of NFAT and NF-kB, and GPR55 internalization. It reduced LPI-induced wound healing in primary human lung microvascular endothelial cells and reversed LPI-inhibited platelet aggregation, suggesting a novel role for GPR55 in platelet and endothelial cell function. CID16020046 is therefore a valuable tool to study GPR55-mediated mechanisms in primary cells and tissues.

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“…Agonist-mediated intracellular Ca 21 release was measured in a 96-well plate format (FlexStation II; Molecular Devices, Sunnyvale, CA), as previously described (Sedej et al, 2012 …”

Section: Intracellular Ca 21 Release Assaysmentioning

confidence: 99%

A Selective Antagonist Reveals a Potential Role of G Protein–Coupled Receptor 55 in Platelet and Endothelial Cell Function

Kargl

Brown

Andersen

et al. 2013

J Pharmacol Exp Ther

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“…The endogenous agonist for CRTh2 is prostaglandin D 2 (PGD 2 ) [12, 13], which is synthesized and released by activated mast cells [14-18]. We recently reported that CRTh2 levels were notably decreased on blood basophils and eosinophils from CSU subjects as compared to healthy controls [19].…”

Section: Introductionmentioning

confidence: 99%

Effects of an Oral CRTh2 Antagonist (AZD1981) on Eosinophil Activity and Symptoms in Chronic Spontaneous Urticaria

Oliver

Chichester

Devine

et al. 2019

Int Arch Allergy Immunol

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Background: Approximately 50% of patients with chronic spontaneous urticaria (CSU) experience symptoms that are not fully controlled by antihistamines, indicating an unmet clinical need. Objective: To evaluate the effects of the selective CRTh2 antagonist AZD1981 on symptoms and targeted leukocytes in adults with persistent CSU despite treatment with H₁-antihistamines. Methods: We performed a single-center, randomized, placebo-controlled study involving adult CSU subjects with symptoms despite daily antihistamines. The subjects underwent a 2-week placebo run-in and 4 weeks of double-blinded therapy with either AZD1981 40 mg TID or placebo, followed by a 2-week placebo washout. The primary objective was to assess the effect of AZD1981 on CSU signs and symptoms. Secondary objectives included the effects of AZD1981 on prostaglandin D₂ (PGD₂)-induced eosinophil shape change, circulating leukocyte subsets, CRTh2 expression on blood leukocytes, and total blood leukocyte histamine content. Results: Twenty-eight subjects were randomized to AZD1981 or placebo, with 26 subjects completing the study. The urticaria activity scores declined during the treatment phase in both groups, and they were significantly reduced in the AZD1981 group at the end of washout. AZD1981 treatment increased circulating eosinophils and significantly impaired PGD₂-mediated eosinophil shape change. CRTh2 surface expression rose significantly on blood basophils during active treatment. No serious adverse events were observed. Conclusions: This is the first study to examine the efficacy of a CRTh2 antagonist in antihistamine-refractory CSU. AZD1981 treatment was well tolerated, effectively inhibited PGD₂-mediated eosinophil shape change, shifted numbers of circulating eosinophils, and reduced weekly itch scores more than hives during treatment and into washout. Further studies are needed to determine whether inhibition of the PGD₂/CRTh2 pathway will be an effective treatment for CSU.

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“…Prostaglandin D 2 is the principal ligand for two receptors, DP1 and DP2 (34), of which both are expressed on the surface of eosinophils (35). At micromolar concentrations, PGD 2 is also an agonist of the thromboxane receptor, TP, which mediates the direct bronchoconstrictor effect of PGD 2 (36).…”

Section: Prostaglandin D2 (Pgd2)mentioning

confidence: 99%

“…Moreover, DP1-dependent eosinophil responses such as migration and production of reactive oxygen species are—to some extent—co-mediated by DP1 (75, 76). On the molecular level, we have shown that DP1 activation is substantially involved in DP2-triggered Ca 2+ signaling in a heterologous expression system and in human peripheral blood eosinophils and, therefore, might be an important regulator of DP2-mediated pro-inflammatory signaling (35). Cooperative signaling of the two receptors also converges in the PGD 2 -induced synthesis of leukotriene C4 synthesis in eosinophils.…”

Section: Prostaglandin D2 (Pgd2)mentioning

confidence: 99%

Prostaglandins and Their Receptors in Eosinophil Function and As Therapeutic Targets

2017

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Of the known prostanoid receptors, human eosinophils express the prostaglandin D2 (PGD2) receptors DP1 [also D-type prostanoid (DP)] and DP2 (also chemoattractant receptor homologous molecule, expressed on Th2 cells), the prostaglandin E2 receptors EP2 and EP4, and the prostacyclin (PGI2) receptor IP. Prostanoids can bind to either one or multiple receptors, characteristically have a short half-life in vivo, and are quickly degraded into metabolites with altered affinity and specificity for a given receptor subtype. Prostanoid receptors signal mainly through G proteins and naturally activate signal transduction pathways according to the G protein subtype that they preferentially interact with. This can lead to the activation of sometimes opposing signaling pathways. In addition, prostanoid signaling is often cell-type specific and also the combination of expressed receptors can influence the outcome of the prostanoid impulse. Accordingly, it is assumed that eosinophils and their (patho-)physiological functions are governed by a sensitive prostanoid signaling network. In this review, we specifically focus on the functions of PGD2, PGE2, and PGI2 and their receptors on eosinophils. We discuss their significance in allergic and non-allergic diseases and summarize potential targets for drug intervention.

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D-type prostanoid receptor enhances the signaling of chemoattractant receptor–homologous molecule expressed on TH2 cells

Cited by 23 publications

References 49 publications

A Selective Antagonist Reveals a Potential Role of G Protein–Coupled Receptor 55 in Platelet and Endothelial Cell Function

A Selective Antagonist Reveals a Potential Role of G Protein–Coupled Receptor 55 in Platelet and Endothelial Cell Function

Effects of an Oral CRTh2 Antagonist (AZD1981) on Eosinophil Activity and Symptoms in Chronic Spontaneous Urticaria

Prostaglandins and Their Receptors in Eosinophil Function and As Therapeutic Targets

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