Cutting edge: agonistic effect of indomethacin on a prostaglandin D2 receptor, CRTH2.
Indomethacin is a widely used nonsteroidal anti-inflammatory drug and is generally known to exhibit its multiple biological functions by inhibiting cyclooxygenases or activating peroxisome proliferator-activated receptors. In this study, we present evidence demonstrating that the novel PGD(2) receptor chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) is another functional target for indomethacin. Indomethacin induced Ca(2+) mobilization in CRTH2-transfected K562 cells at submicromolar concentrations (approximate EC(50), 50 nM) in a G(alphai)-dependent manner as PGD(2) did. Other nonsteroidal anti-inflammatory drugs (aspirin, sulindac, diclofenac, and acemetacin) had no such effect even at micromolar concentrations. In chemotaxis assay, three CRTH2-expressing cell types, Th2 cells, eosinophils, and basophils, were all significantly attracted by indomethacin (EC(50), 50-500 nM) as well as by PGD(2) (EC(50), 2-20 nM), and the effects of indomethacin were blocked by anti-CRTH2 mAb. These results suggest the involvement of CRTH2 in mediating some of therapeutic and/or unwanted side effects of indomethacin, independently of cyclooxygenases and peroxisome proliferator-activated receptors.
Hirai
Hiroyuki
H
R&D Center, BML, 1361-1 Matoba, Kawagoe, Saitama 350-1101, Japan.
Tanaka
Kazuya
K
Takano
Shoichi
S
Ichimasa
Michiko
M
Nakamura
Masataka
M
Nagata
Kinya
K
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D019169:Jurkat Cells; D020014:K562 Cells; D015230:Prostaglandin D2 / Q000378:metabolism* / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D011982:Receptors, Prostaglandin / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014162:Transfection
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D015230:Prostaglandin D2; D002118:Calcium; D007213:Indomethacin; C036293:prostaglandin D2 receptor