Differential modulation of human basophil functions through prostaglandin D2 receptors DP and chemoattractant receptor-homologous molecule expressed on Th2 cells/DP2

Authors

  • C. Yoshimura-Uchiyama,

    1. Departments of *Allergy and Rheumatology, †Pediatrics, ‡Laboratory Medicine, §Molecular Preventive Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan, ¶Respiratory Diseases Research, Research Center Kyoto, Kyoto, Japan∥Department of Bioregulatory Function, University of Tokyo Graduate School of Medicine, Tokyo, Japan
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  • M. Iikura,

    1. Departments of *Allergy and Rheumatology, †Pediatrics, ‡Laboratory Medicine, §Molecular Preventive Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan, ¶Respiratory Diseases Research, Research Center Kyoto, Kyoto, Japan∥Department of Bioregulatory Function, University of Tokyo Graduate School of Medicine, Tokyo, Japan
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  • M. Yamaguchi,

    1. Departments of *Allergy and Rheumatology, †Pediatrics, ‡Laboratory Medicine, §Molecular Preventive Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan, ¶Respiratory Diseases Research, Research Center Kyoto, Kyoto, Japan∥Department of Bioregulatory Function, University of Tokyo Graduate School of Medicine, Tokyo, Japan
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  • H. Nagase,

    1. Departments of *Allergy and Rheumatology, †Pediatrics, ‡Laboratory Medicine, §Molecular Preventive Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan, ¶Respiratory Diseases Research, Research Center Kyoto, Kyoto, Japan∥Department of Bioregulatory Function, University of Tokyo Graduate School of Medicine, Tokyo, Japan
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  • A. Ishii,

    1. Departments of *Allergy and Rheumatology, †Pediatrics, ‡Laboratory Medicine, §Molecular Preventive Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan, ¶Respiratory Diseases Research, Research Center Kyoto, Kyoto, Japan∥Department of Bioregulatory Function, University of Tokyo Graduate School of Medicine, Tokyo, Japan
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  • K. Matsushima,

    1. Departments of *Allergy and Rheumatology, †Pediatrics, ‡Laboratory Medicine, §Molecular Preventive Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan, ¶Respiratory Diseases Research, Research Center Kyoto, Kyoto, Japan∥Department of Bioregulatory Function, University of Tokyo Graduate School of Medicine, Tokyo, Japan
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  • K. Yamamoto,

    1. Departments of *Allergy and Rheumatology, †Pediatrics, ‡Laboratory Medicine, §Molecular Preventive Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan, ¶Respiratory Diseases Research, Research Center Kyoto, Kyoto, Japan∥Department of Bioregulatory Function, University of Tokyo Graduate School of Medicine, Tokyo, Japan
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  • M. Shichijo,

    1. Departments of *Allergy and Rheumatology, †Pediatrics, ‡Laboratory Medicine, §Molecular Preventive Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan, ¶Respiratory Diseases Research, Research Center Kyoto, Kyoto, Japan∥Department of Bioregulatory Function, University of Tokyo Graduate School of Medicine, Tokyo, Japan
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  • K. B. Bacon,

    1. Departments of *Allergy and Rheumatology, †Pediatrics, ‡Laboratory Medicine, §Molecular Preventive Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan, ¶Respiratory Diseases Research, Research Center Kyoto, Kyoto, Japan∥Department of Bioregulatory Function, University of Tokyo Graduate School of Medicine, Tokyo, Japan
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  • K. Hirai

    1. Departments of *Allergy and Rheumatology, †Pediatrics, ‡Laboratory Medicine, §Molecular Preventive Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan, ¶Respiratory Diseases Research, Research Center Kyoto, Kyoto, Japan∥Department of Bioregulatory Function, University of Tokyo Graduate School of Medicine, Tokyo, Japan
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Koichi Hirai, Department of Bioregulatory Function, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
E-mail: hiraiko-tky@umin.ac.jp

Summary

Background Both prostaglandin (PG) D receptor (DP) and CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells)/DP2 are high-affinity receptors for PGD2. Previous studies have demonstrated that PGD2 enhances releasability and induces CRTH2/DP2-mediated migration in human basophils, but the precise effects of PGD2 on basophils as well as receptor usage have not been fully clarified.

Objective We comprehensively explored the roles of DP and CRTH2/DP2 in basophil functions by using selective agonists and antagonists for each receptor.

Methods DP and CRTH2/DP2 transcripts were quantified by real-time PCR. We studied the effects of selective agonists (DP: BW245C; CRTH2/DP2: 13,14-dihydro-15-keto (DK)-PGD2) and/or antagonists (DP: BWA868C; CRTH2/DP2: ramatroban) on Ca2+ mobilization, migration, degranulation, CD11b expression and survival of human basophils.

Results Basophils expressed transcripts of both DP and CRTH2/DP2, but the levels of CRTH2/DP2 transcripts were ca. 100-fold higher compared with DP transcripts. Ca2+ influx was induced in basophils by either PGD2 or DK-PGD2/CRTH2 agonist but not by BW245C/DP agonist. Basophils treated with PGD2 were completely desensitized to subsequent stimulation with DK-PGD2, but not vice versa. DK-PGD2 as well as PGD2 up-regulated CD11b expression, induced migration and enhanced degranulation, and those effects were completely antagonized by ramatroban/CRTH2 antagonist. In contrast, BW245C/DP agonist exhibited an inhibitory effect on basophil migration and IgE-mediated degranulation, and the migration inhibitory effect was effectively antagonized by BWA868C/DP antagonist. On the other hand, while PGD2 significantly shortened the basophil life-span, neither DK-PGD2/CRTH2 agonist nor BW245C/DP agonist did.

Conclusion CRTH2/DP2 is primarily responsible for the pro-inflammatory effects of PGD2 on human basophils, while DP introduces negative signals capable of antagonizing the effects of CRTH2/DP2 in these cells. The effects of PGD2 on longevity imply a mechanism(s) other than via DP or CRTH2/DP2. CRTH2/DP2 on basophils may afford opportunities for therapeutic targeting in allergic inflammation.

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