Prostaglandin D2 and Interleukin-5 Reduce Crth2 Surface Expression on Human Eosinophils

Hamada, Kazuyuki; Yamada, Yoshiyuki; Kamada, Yumiko; Ueki, Shigeharu; Yamaguchi, K.; Oyamada, Hirokazu; Fujita, Mutsuhiro; Usami, Atsuko; Chiba, Takahito; Kanda, Akira; Kayaba, Hiroyuki; Chihara, Junichi

doi:10.1111/j.1440-1592.2004.00323.x

Cited by 19 publications

(16 citation statements)

References 23 publications

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“…We recently reported that CRTh2 levels were notably decreased on blood basophils and eosinophils from CSU subjects as compared to healthy controls [19]. This finding is consistent with ongoing in vivo receptor-ligand engagement, leading to CRTh2 receptor internalization [20, 21]. …”

Section: Introductionsupporting

confidence: 69%

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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Section: Introductionsupporting

confidence: 69%

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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“…philia. In contrast, IL-5 has been shown to desensitize eosinophils to PGD 2 by down-regulating the expression of CRTH2 (Hamada et al, 2004). Similar phenomenon has been observed in vivo; eosinophils isolated from IL-5 transgenic mice cannot bind to PGD 2 (Hirai et al, 2003).…”

Section: Discussionmentioning

confidence: 67%

Prostaglandin D₂-Induced Eosinophilic Airway Inflammation Is Mediated by CRTH2 Receptor

Shiraishi

Asano²,

Nakajima³

et al. 2004

J Pharmacol Exp Ther

106

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Mast cell-derived prostaglandin D 2 (PGD 2 ) is one of the essential modulators of eosinophilic airway inflammation in asthma and allergic rhinitis. Two G protein-coupled receptors for PGD 2 , prostaglandin D 2 receptor (DP) and chemoattractant receptorhomologous molecule expressed on Th 2 cells (CRTH2), are both expressed on the surface of eosinophils, and CRTH2 has been demonstrated to mediate PGD 2 -induced eosinophil mobilization in vitro. However, it has not yet been determined whether PGD 2 and its receptors mediate in vivo eosinophil trafficking into the airways or other organs. We demonstrated that intratracheal administration of PGD 2 in rats pretreated with systemic interleukin-5 (IL-5) injection induced marked airway eosinophilia, determined by the differential counts of cells in bronchoalveolar lavage (BAL) fluid and lung histology, within 2 h. Systemic IL-5 alone significantly increased the number of eosinophils in the peripheral blood but showed no effect on airway eosinophilia. Three CRTH2-specific agonists (13,14-dihydro-15-keto-PGD 2 , 11-deoxy-11-methylene-15-keto-PGD 2 , and indomethacin) demonstrated equivalent induction of BAL eosinophilia to that of PGD 2 , but a DP agonist (BW 245C [5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)-hydantoin]) or a thromboxane A 2 receptor (TP) agonist ([1S-1␣,2␤(5Z), 3␣(1E,3R*),4␣)]-7-[3-(3-hydroxy-4-(4Ј-iodophenoxy)-1-butenyl)-7-oxabicyclo-[2.2.1]heptan-2-yl]-5-heptenoic acid) showed no effect. PGD 2 or CRTH2 agonist-induced BAL eosinophilia was almost completely inhibited by pretreatment with a CRTH2/TP antagonist, ramatroban [BAY-u3405; (ϩ)-(3R)-3-(4-fluorobenzenesulfonamido)-1,2,3,4-tetra-hydrocarbazole-9-propionic acid], whereas a TP-specific antagonist, SQ29,, or a DP-specific antagonist, BW A868C [3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexy-2-hydroxyethylamino)-hydantoin], did not inhibit the effects of PGD 2 . These results suggest that CRTH2 plays a significant role in the eosinophil trafficking from the bloodstream into the airways in PGD 2 -related airway inflammation.

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“…Several reports have demonstrated the down-modulation upon activation [10,29,30,31]. CRTH2 expression on human Th 2 cells was reduced upon CD3/CD28 stimulation [29] and on human eosinophils upon either PGD 2 or IL-5 activation [30].…”

Section: Discussionmentioning

confidence: 99%

Expression and Characterization of PGD<sub>2</sub> Receptors in Chronic Rhinosinusitis: Modulation of DP and CRTH2 by PGD<sub>2</sub>

Yamamoto¹,

Okano²,

Fujiwara³

et al. 2008

Int Arch Allergy Immunol

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Background: Prostaglandin D₂ (PGD₂) participates in airway inflammation. We reported that levels of hematopoietic-type PGD₂ synthase (h-PGDS) in sinonasal tissues may play an important role in the pathophysiology of chronic rhinosinusitis (CRS). Two PGD₂ receptors have been isolated, DP and CRTH2, but whether they participate in CRS remains unclear. We sought to determine the expression and characterization of DP and CRTH2 in CRS. Methods: Expression of DP and CRTH2 in nasal polyps (NP) and uncinate process mucosae (UPM) was examined by in situ hybridization and immunohistochemistry and evaluated by real-time quantitative PCR. h-PGDS, IL-5, eotaxin and RANTES expression was also determined. In addition, the effect of PGD₂ on the expression of both receptors in UPM was assessed. Results: DP was widely expressed, not only in infiltrating inflammatory cells but also in constitutive cells such as vascular endothelial cells and ciliated columnar epithelia. CRTH2 was selectively expressed in inflammatory cells and some glands. Significantly greater levels of DP mRNA and conversely decreased levels of CRTH2 mRNA were observed in NP compared with UPM. DP and CRTH2 mRNA levels were not only positively and inversely correlated with levels of h-PGDS but also with eotaxin, respectively. Furthermore, addition of PGD₂ significantly increased DP expression and conversely reduced CRTH2 expression in UPM. Conclusions: These results suggest that distinct expression of DP and CRTH2 is associated with the pathophysiology of CRS, including NP formation, and the expression of these receptors may be regulated by h-PGDS and PGD₂.

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Prostaglandin D2 and Interleukin-5 Reduce Crth2 Surface Expression on Human Eosinophils

Cited by 19 publications

References 23 publications

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

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

Prostaglandin D₂-Induced Eosinophilic Airway Inflammation Is Mediated by CRTH2 Receptor

Expression and Characterization of PGD<sub>2</sub> Receptors in Chronic Rhinosinusitis: Modulation of DP and CRTH2 by PGD<sub>2</sub>

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Prostaglandin D2 and Interleukin-5 Reduce Crth2 Surface Expression on Human Eosinophils

Cited by 19 publications

References 23 publications

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

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

Prostaglandin D2-Induced Eosinophilic Airway Inflammation Is Mediated by CRTH2 Receptor

Expression and Characterization of PGD<sub>2</sub> Receptors in Chronic Rhinosinusitis: Modulation of DP and CRTH2 by PGD<sub>2</sub>

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Prostaglandin D₂-Induced Eosinophilic Airway Inflammation Is Mediated by CRTH2 Receptor