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Cutting Edge |
*
R&D Center, BML, Saitama, Japan;
Graduate School of Science and Engineering and
Department of Environmental Sciences, Faculty of Science, Ibaraki University, Ibaraki, Japan; and
Human Gene Sciences Center, Tokyo Medical and Dental University, Tokyo, Japan
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 PGD2 receptor chemoattractant
receptor-homologous molecule expressed on Th2 cells (CRTH2) is another
functional target for indomethacin. Indomethacin induced
Ca2+ mobilization in CRTH2-transfected K562 cells at
submicromolar concentrations (approximate EC50, 50 nM) in a
G
i-dependent manner as PGD2 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 (EC50, 50–500 nM)
as well as by PGD2 (EC50, 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.
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