Selective modulation of chemokinesis, degranulation, and apoptosis in eosinophils through the PGD sub(2) receptors CRTH2 and DP

• Published in: Journal of allergy and clinical immunology Vol. 108; no. 6; pp. 982 - 988
• Main Authors: Gervais, F G, Cruz, RPG, Chateauneuf, A, Gale, S, Sawyer, N, Nantel, F, Metters, K M, O'Neill, G P
• Format: Journal Article
• Language: English
• Published: 01-12-2001
• Subjects: prostaglandin D2 receptors; prostanoids
• ISSN: 0091-6749
• DOI: 10.1067/mai.2001.119919

PGD2 is the major prostanoid released by mast cells during an allergic response. Its role in the allergic response, however, remains unclear. Because the accumulation of eosinophils is a feature of allergic reactions, we investigated the role of PGD2 in the modulation of eosinophil function. Circulating human eosinophils were isolated and challenged with PGD2. The effects of PGD2 on various eosinophil functions were then analyzed. PGD2 binds with high affinity preferentially to 2 receptors, DP and chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2). We show that both DP and CRTH2 are detectable on circulating eosinophils. We demonstrate that PGD2 (1-10 nmol/L) induces a rapid change in human eosinophil morphology and an increase in chemokinesis and promotes eosinophil degranulation. These effects are induced by the CRTH2-selective agonist 13-14-dihydro-15-keto-PGD2 (DK-PGD2) but not by the DP-selective agonist BW245C. These results suggest a role for CRTH2 in the modulation of eosinophil movement and in triggering the release of cytotoxic proteins. Finally, we demonstrate that BW245C, but not DK-PGD2, can delay the onset of apoptosis in cultured eosinophils, presumably through interaction with DP. These data support the hypothesis that PGD2 controls eosinophil functions through 2 pharmacologically distinct receptors with independent functions. Blockade of PGD2-mediated effects on human eosinophils may reduce the damage caused by these cells during an allergic response, but inhibition of both receptors may be required.