Monneret G, Gravel S, Diamond M, Rokach J, Powell W S
Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, QC, Canada.
Blood. 2001 Sep 15;98(6):1942-8. doi: 10.1182/blood.v98.6.1942.
Prostaglandin D2 (PGD2) is released following exposure of asthmatics to allergen and acts via the adenylyl cyclase-coupled receptor for PGD2 (DP receptor). In this study, it is reported that human eosinophils possess this receptor, which would be expected to inhibit their activation. In contrast, it was found that prostaglandin D2 is a potent stimulator of eosinophil chemotaxis, actin polymerization, CD11b expression, and L-selectin shedding. These responses are specific for eosinophils, as neutrophils display little or no response to prostaglandin D2. They were not due to interaction with receptors for other prostanoids, as prostaglandins E2 and F(2alpha), U46619 (a thromboxane A2 analogue), and carbaprostacyclin (a prostacyclin analogue) displayed little or no activity. Furthermore, they were not shared by the selective DP receptor agonist BW245C and were not prevented by the selective DP receptor antagonist BWA868C, indicating that they were not mediated by DP receptors. In contrast, the prostaglandin D2 metabolite 13,14-dihydro-15-oxoprostaglandin D2 induced eosinophil activation but did not stimulate DP receptor-mediated adenosine 3',5'-cyclic monophosphate (cAMP) formation. These results indicate that in addition to the classic inhibitory DP1 receptor, eosinophils possess a second, novel DP2 receptor that is associated with PGD2-induced cell activation. These 2 receptors appear to interact to regulate eosinophil responses to PGD2, as blockade of DP1 receptor-mediated cAMP production by BWA868C resulted in enhanced DP2 receptor-mediated stimulation of CD11b expression. The balance between DP1 and DP2 receptors could determine the degree to which prostaglandin D2 can activate eosinophils and may play a role in eosinophil recruitment in asthma.
哮喘患者接触变应原后会释放前列腺素D2（PGD2），它通过与腺苷酸环化酶偶联的前列腺素D2受体（DP受体）发挥作用。在本研究中，有报道称人类嗜酸性粒细胞拥有该受体，预计该受体可抑制嗜酸性粒细胞的活化。然而，研究发现前列腺素D2却是嗜酸性粒细胞趋化、肌动蛋白聚合、CD11b表达及L-选择素脱落的强效刺激物。这些反应对嗜酸性粒细胞具有特异性，因为中性粒细胞对前列腺素D2几乎没有反应。这些反应并非由与其他前列腺素受体的相互作用所致，因为前列腺素E2、F（2α）、U46619（一种血栓素A2类似物）和卡前列环素（一种前列环素类似物）几乎没有活性。此外，选择性DP受体激动剂BW245C也不具备这些作用，选择性DP受体拮抗剂BWA868C也无法阻止这些反应，这表明它们并非由DP受体介导。相反，前列腺素D2代谢产物13,14-二氢-15-氧代前列腺素D2可诱导嗜酸性粒细胞活化，但不会刺激DP受体介导的3',5'-环磷酸腺苷（cAMP）生成。这些结果表明，除了经典的抑制性DP1受体外，嗜酸性粒细胞还拥有第二种新型DP2受体，该受体与PGD2诱导的细胞活化相关。这两种受体似乎相互作用以调节嗜酸性粒细胞对PGD2的反应，因为BWA868C对DP1受体介导的cAMP生成的阻断导致DP2受体介导的CD11b表达刺激增强。DP1和DP2受体之间的平衡可能决定前列腺素D2激活嗜酸性粒细胞的程度，并可能在哮喘中嗜酸性粒细胞募集过程中发挥作用。
