Cutting edge:: Agonistic effect of indomethacin on a prostaglandin D2 receptor, CRTH2
Cutting edge:: Agonistic effect of indomethacin on a prostaglandin D2 receptor, CRTH2
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DOI：
10.4049/jimmunol.168.3.981
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发表时间：
2002-02-01
影响因子：
4.4
通讯作者：
Nagata, K
中科院分区：
文献类型：
--
作者：
Hirai, H;Tanaka, K;Nagata, K
吲哚美辛是一种应用广泛的非甾体抗炎药，通过抑制环氧合酶或激活过氧化物酶体增殖物激活受体发挥多种生物学功能。在这项研究中，我们提出的证据表明，表达在Th2细胞上的新型PGD(2)受体趋化因子受体同源分子(CRTH2)是吲哚美辛的另一个功能靶点。亚微摩尔浓度(约EC50，50 nM)的吲哚美辛与PGD(2)一样，以G(Alphai)依赖的方式诱导CRTH2转染组K562细胞内钙离子的动员。其他非类固醇抗炎药(阿司匹林、舒林酸、双氯芬酸和阿西美辛)即使在微摩尔浓度下也没有这种作用。趋化实验中，表达CRTH2的Th2细胞、嗜酸性粒细胞和嗜碱性粒细胞均被消炎痛(EC50，50-500 nM)和PGD(2)(EC50，2-20 nM)显著吸引，抗CRTH2单抗可阻断消炎痛的作用。这些结果表明，CRTH2参与介导了吲哚美辛的一些治疗和/或不良副作用，而不依赖于环氧合酶和过氧化物酶体增殖物激活受体。
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 Ca2+ mobilization in CRTH2-transfected K562 cells at submicromolar concentrations (approximate EC50, 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 (EC50, 50-500 nM) as well as by PGD(2) (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.