Chemoattractant receptor-homologous molecule expressed on Th2 cells activation in vivo increases blood leukocyte counts and its blockade abrogates 13,14-dihydro-15-keto-prostaglandin D2-induced eosinophilia in rats.
We cloned, expressed, and characterized in vitro and in vivo the gene encoding the rat ortholog of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), a G protein-coupled receptor for prostaglandin D2 (PGD2). Quantitative reverse transcription-polymerase chain reaction analysis demonstrated highest CRTH2 expression in the lung, brain, ovary, and spleen. Pharmacologically, rat CRTH2 stably transfected in mouse preB lymphoma L1.2 cells behaved very similar compared with the mouse and human orthologs, showing a binding affinity for PGD2 of 11 nM, a functional calcium mobilization when exposed to agonist, and similar sensitivity to agonists and antagonists. In vivo, selective activation of CRTH2 by 13,14-dihydro-15-keto (DK)-PGD2 injection into rats led to a dose- and time-dependent increase of the number of leukocytes in the peripheral blood. Specifically, eosinophils, lymphocytes, and neutrophils were recruited with maximum effects seen 60 min after the injection of 300 microg of DK-PGD2 per rat. Pretreatment of the animals with the CRTH2/thromboxane A2 receptor antagonist, ramatroban, completely abrogated DK-PGD2-induced eosinophilia, suggesting that CRTH2 might have a physiological and/or pathophysiological role in controlling leukocyte migration.
Shichijo
Michitaka
M
Research Center Kyoto, Respiratory Research, Bayer Yakuhin, Ltd., 6-5-1-3 Kunimidai, Kizu-cho, Sorakugun, 619-0216 Kyoto, Japan.
Sugimoto
Hiromi
H
Nagao
Koichi
K
Inbe
Hisayo
H
Encinas
Jeffrey A
JA
Takeshita
Keisuke
K
Bacon
Kevin B
KB
Gantner
Florian
F
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001853:Bone Marrow / Q000187:drug effects* / Q000502:physiology; D002227:Carbazoles / Q000494:pharmacology; D003001:Cloning, Molecular; D004802:Eosinophilia / Q000139:chemically induced*; D006801:Humans; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011982:Receptors, Prostaglandin; D017386:Sequence Homology, Amino Acid; D013449:Sulfonamides / Q000494:pharmacology; D018418:Th2 Cells / Q000378:metabolism
D002227:Carbazoles; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013449:Sulfonamides; C034832:13,14-dihydro-15-ketoprostaglandin D2; C063119:ramatroban; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor