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Differential modulation of human basophil functions through prostaglandin D 2 receptors DP and chemoattractant receptor‐homologous molecule expressed on Th2 cells/DP2
Author(s) -
YoshimuraUchiyama C.,
Iikura M.,
Yamaguchi M.,
Nagase H.,
Ishii A.,
Matsushima K.,
Yamamoto K.,
Shichijo M.,
Bacon K. B.,
Hirai K.
Publication year - 2004
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/j.1365-2222.2004.02027.x
Subject(s) - prostaglandin d2 , degranulation , receptor , chemotaxis , basophil , agonist , microbiology and biotechnology , prostaglandin , chemistry , immunoglobulin e , biology , immunology , biochemistry , antibody
Summary Background Both prostaglandin (PG) D receptor (DP) and CRTH2 (chemoattractant receptor‐homologous molecule expressed on Th2 cells)/DP2 are high‐affinity receptors for PGD 2 . Previous studies have demonstrated that PGD 2 enhances releasability and induces CRTH2/DP2‐mediated migration in human basophils, but the precise effects of PGD 2 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)‐PGD 2 ) and/or antagonists (DP: BWA868C; CRTH2/DP2: ramatroban) on Ca 2+ 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. Ca 2+ influx was induced in basophils by either PGD 2 or DK‐PGD 2 /CRTH2 agonist but not by BW245C/DP agonist. Basophils treated with PGD 2 were completely desensitized to subsequent stimulation with DK‐PGD 2 , but not vice versa . DK‐PGD 2 as well as PGD 2 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 PGD 2 significantly shortened the basophil life‐span, neither DK‐PGD 2 /CRTH2 agonist nor BW245C/DP agonist did. Conclusion CRTH2/DP2 is primarily responsible for the pro‐inflammatory effects of PGD 2 on human basophils, while DP introduces negative signals capable of antagonizing the effects of CRTH2/DP2 in these cells. The effects of PGD 2 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.