Selective modulation of chemokinesis, degranulation, and apoptosis in eosinophils through the PGD2 receptors CRTH2 and DP.
BACKGROUND
PGD(2) is the major prostanoid released by mast cells during an allergic response. Its role in the allergic response, however, remains unclear.


OBJECTIVE
Because the accumulation of eosinophils is a feature of allergic reactions, we investigated the role of PGD(2) in the modulation of eosinophil function.


METHODS
Circulating human eosinophils were isolated and challenged with PGD(2). The effects of PGD(2) on various eosinophil functions were then analyzed.


RESULTS
PGD(2) binds with high affinity preferentially to 2 receptors, DP and chemoattractant receptor-homologous molecule expressed on T(H)2 cells (CRTH2). We show that both DP and CRTH2 are detectable on circulating eosinophils. We demonstrate that PGD(2) (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-PGD(2) (DK-PGD(2)) 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-PGD(2), can delay the onset of apoptosis in cultured eosinophils, presumably through interaction with DP.


CONCLUSIONS
These data support the hypothesis that PGD(2) controls eosinophil functions through 2 pharmacologically distinct receptors with independent functions. Blockade of PGD(2)-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.
Gervais
F G
FG
Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada.
Cruz
R P
RP
Chateauneuf
A
A
Gale
S
S
Sawyer
N
N
Nantel
F
F
Metters
K M
KM
O'neill
G P
GP
D017209:Apoptosis; D015550:Cell Degranulation / Q000187:drug effects; D002465:Cell Movement; D002478:Cells, Cultured; D004804:Eosinophils / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D006801:Humans; D015230:Prostaglandin D2 / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology*; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000502:physiology*
D012333:RNA, Messenger; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor