Pharmacological characterization of guinea pig chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2).
Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), a G protein-coupled receptor activated by prostaglandin D(2) (PGD(2)), has been identified as a receptor expressed on cell types critical to the pathogenesis of asthma. The cDNA encoding guinea pig CRTH2 was cloned and mRNA expression examined in selected tissues. Transcript profiling of guinea pig CRTH2 indicated relatively high levels of expression in bone marrow, intermediate levels in brain and relatively low levels in lung, spleen, thymus, lymph node, etc. Characterization of the molecular pharmacology of guinea pig CRTH2 revealed that guinea pig CRTH2 exhibited a greater affinity for Delta(12)-PGJ(2), a stable PGD(2) metabolite relative to human CRTH2. The CRTH2 selective agonists 13,14-dihydro-15-keto PGD(2) and Delta(12)-PGJ(2) induced the recruitment of eosinophils following intradermal administration of these ligands in guinea pigs. Chemotaxis of guinea pig eosinophils was elicited by either PGD(2) or Delta(12)-PGJ(2), and was abolished by a CRTH2-specific antagonist. These results indicate that PGD(2) and the stable metabolite, Delta(12)-PGJ(2), play important roles in CRTH2 activation in the guinea pig.
Liu
Fang
F
Department of Inflammation, Millennium Pharmaceutical Inc., Cambridge, MA 02139, USA.
Gonzalo
Jose Angel
JA
Manning
Stephen
S
O'Connell
Laura E
LE
Fedyk
Eric R
ER
Burke
Kristine E
KE
Elder
Amy M
AM
Pulido
Jacqueline C
JC
Cao
Wei
W
Tayber
Olga
O
Qiu
Yubin
Y
Ghosh
Shomir
S
Ocain
Timothy D
TD
Hodge
Martin R
MR
Suzuki-Yagawa
Yuriko
Y
D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002634:Chemotaxis, Leukocyte; D003001:Cloning, Molecular; D017931:DNA Primers; D018076:DNA, Complementary; D004804:Eosinophils / Q000166:cytology; D006168:Guinea Pigs; D006801:Humans; D008168:Lung / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D008297:Male; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism
D017931:DNA Primers; D018076:DNA, Complementary; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D002118:Calcium; C036293:prostaglandin D2 receptor