Schratl Petra, Royer Julia F, Kostenis Evi, Ulven Trond, Sturm Eva M, Waldhoer Maria, Hoefler Gerald, Schuligoi Rufina, Lippe Irmgard Th, Peskar Bernhard A, Heinemann Akos
Institute of Experimental and Clinical Pharmacology, Medical University Graz, Graz, Austria.
J Immunol. 2007 Oct 1;179(7):4792-9. doi: 10.4049/jimmunol.179.7.4792.
Prostaglandin (PG) D2 is a major mast cell product that acts via two receptors, the D-type prostanoid (DP) and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) receptors. Whereas CRTH2 mediates the chemotaxis of eosinophils, basophils, and Th2 lymphocytes, the role of DP has remained unclear. We report in this study that, in addition to CRTH2, the DP receptor plays an important role in eosinophil trafficking. First, we investigated the release of eosinophils from bone marrow using the in situ perfused guinea pig hind limb preparation. PGD2 induced the rapid release of eosinophils from bone marrow and this effect was inhibited by either the DP receptor antagonist BWA868c or the CRTH2 receptor antagonist ramatroban. In contrast, BWA868c did not inhibit the release of bone marrow eosinophils when this was induced by the CRTH2-selective agonist 13,14-dihydro-15-keto-PGD2. In additional experiments, we isolated bone marrow eosinophils from the femoral cavity and found that these cells migrated toward PGD2. We also observed that BWA868c inhibited this response to a similar extent as ramatroban. Finally, using immunohistochemistry we could demonstrate that eosinophils in human bone marrow specimens expressed DP and CRTH2 receptors at similar levels. Eosinophils isolated from human peripheral blood likewise expressed DP receptor protein but at lower levels than CRTH2. In agreement with this, the chemotaxis of human peripheral blood eosinophils was inhibited both by BWA868c and ramatroban. These findings suggest that DP receptors comediate with CRTH2 the mobilization of eosinophils from bone marrow and their chemotaxis, which might provide the rationale for DP antagonists in the treatment of allergic disease.
前列腺素（PG）D2是肥大细胞的主要产物，它通过两种受体发挥作用，即D型前列腺素受体（DP）和Th2细胞上表达的趋化因子受体同源分子（CRTH2）。虽然CRTH2介导嗜酸性粒细胞、嗜碱性粒细胞和Th2淋巴细胞的趋化作用，但DP的作用仍不清楚。我们在本研究中报告，除CRTH2外，DP受体在嗜酸性粒细胞迁移中也起重要作用。首先，我们使用原位灌注豚鼠后肢制备方法研究了骨髓中嗜酸性粒细胞的释放。PGD2诱导骨髓中嗜酸性粒细胞快速释放，而这种作用被DP受体拮抗剂BWA868c或CRTH2受体拮抗剂拉马曲班抑制。相反，当骨髓嗜酸性粒细胞的释放由CRTH2选择性激动剂13,14-二氢-15-酮-PGD2诱导时，BWA868c并不抑制这种释放。在另外的实验中，我们从股骨腔分离出骨髓嗜酸性粒细胞，发现这些细胞向PGD2迁移。我们还观察到BWA868c对这种反应的抑制程度与拉马曲班相似。最后，通过免疫组织化学我们能够证明，人类骨髓标本中的嗜酸性粒细胞表达DP和CRTH2受体的水平相似。从人类外周血分离出的嗜酸性粒细胞同样表达DP受体蛋白，但水平低于CRTH2。与此一致的是，BWA868c和拉马曲班均抑制人类外周血嗜酸性粒细胞的趋化作用。这些发现表明，DP受体与CRTH2共同介导骨髓中嗜酸性粒细胞的动员及其趋化作用，这可能为DP拮抗剂治疗过敏性疾病提供理论依据。
