Prostaglandin D2 causes preferential induction of proinflammatory Th2 cytokine production through an action on chemoattractant receptor-like molecule expressed on Th2 cells
Prostaglandin D2 causes preferential induction of proinflammatory Th2 cytokine production through an action on chemoattractant receptor-like molecule expressed on Th2 cells
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DOI：
10.4049/jimmunol.175.10.6531
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发表时间：
2005-11-15
影响因子：
4.4
通讯作者：
Pettipher, R
中科院分区：
文献类型：
--
作者：
Xue, LZ;Gyles, SL;Pettipher, R
由肥大细胞产生的PGD(2)在过敏性炎症部位被检测到高浓度。它通过与D前列腺素受体（DP）和表达于Th2细胞（CRTH2）受体上的趋化受体样分子（chemattractant receptor-like molecule）相互作用，刺激血管和其他炎症反应。PGD(2)在介导过敏反应中的重要作用是基于观察到在过表达人PGD2合成酶的转基因小鼠的过敏原挑战气道中明显增强嗜酸性肺炎症和细胞因子的产生，PGD2可以在体外从CD3/ cd28共刺激的Th2细胞中增强Th2细胞因子的产生。在本研究中，我们研究了PGD(2)在没有共刺激的情况下是否有能力刺激Th2细胞因子的产生。在变应性炎症部位发现的浓度下，PGD(2)以剂量依赖的方式优先诱导人Th2细胞产生IL-4、IL-5和IL-13，而不影响抗炎细胞因子IL-10的水平。基因转录在刺激后2小时内达到峰值，蛋白质释放在刺激后8小时达到峰值。选择性CRTH2激动剂13,14-二氢-15-酮-PGD(2)可以模拟PGD(2)的作用，但选择性DIP激动剂BW245C不能模拟PGD(2)的作用，表明这种刺激是由CRTH2介导的，而不是DP。双CRTH2/血栓素样前列腺素受体拮抗剂Ramatroban可显著抑制PGD诱导的Th2细胞因子的产生(2)，而选择性血栓素样前列腺素受体拮抗剂SQ29548则无作用。这些数据表明，PGD(2)在没有任何其他共刺激的情况下，通过CRTH2依赖性机制优先上调人Th2细胞中促炎细胞因子的产生，并突出了CRTH2拮抗剂在治疗过敏性疾病中的潜在作用。
PGD(2), produced by mast cells, has been detected in high concentrations at sites of allergic inflammation. It can stimulate vascular and other inflammatory responses by interaction with D prostanoid receptor (DP) and chemoattractant receptor-like molecule expressed on Th2 cells (CRTH2) receptors. A significant role for PGD(2) in mediating allergic responses has been suggested based on the observation that enhanced eosinophilic lung inflammation and cytokine production is apparent in the allergen-challenged airways of transgenic mice overexpressing human PGD2 synthase, and PGD2 can enhance Th2 cytokine production in vitro from CD3/CD28-costimulated Th2 cells. In the present study, we investigated whether PGD(2) has the ability to stimulate Th2 cytokine production in the absence of costimulation. At concentrations found at sites of allergic inflammation, PGD(2) preferentially elicited the production of IL-4, IL-5, and IL-13 by human Th2 cells in a dose-dependent manner without affecting the level of the anti-inflammatory cytokine IL-10. Gene transcription peaked within 2 h, and protein release peaked similar to 8 h after stimulation. The effect of PGD(2) was mimicked by the selective CRTH2 agonist 13,14-dihydro-15-keto-PGD(2) but not by the selective DIP agonist BW245C, suggesting that the stimulation is mediated by CRTH2 and not DP. Ramatroban, a dual CRTH2/thromboxane-like prostanoid receptor antagonist, markedly inhibited Th2 cytokine production induced by PGD(2), while the selective thromboxane-like prostanoid receptor antagonist SQ29548 was without effect. These data suggest that PGD(2) preferentially up-regulates proinflammatory cytokine production in human Th2 cells through a CRTH2-dependent mechanism in the absence of any other costimulation and highlight the potential utility of CRTH2 antagonists in the treatment of allergic diseases.