15-Deoxy-Δ12,1412,14-prostaglandins D2 and J2 Are Potent Activators of Human Eosinophils

Abstract

15-Deoxy-Δ12,14-PDJ2 (15d-PGJ2) is a degradation product of PGD2 that has been proposed as an anti-inflammatory compound because of its various inhibitory effects, some of which are mediated by peroxisome proliferator-activated receptor-γ. In contrast to its reported inhibitory effects on macrophages and other cells, we found that this compound is a potent activator of eosinophils, inducing calcium mobilization, actin polymerization, and CD11b expression. It is selective for eosinophils, having little or no effect on neutrophils or monocytes. 15d-PGJ2 has an EC50 of ∼10 nM, similar to that of its precursor, PGD2. The concentrations of 15d-PGJ2 required to activate eosinophils are thus much lower than those required for its anti-inflammatory effects (usually micromolar). 15-Deoxy-Δ12,14-prostaglandin D2 (15d-PGD2) is also a potent activator of eosinophils, with an EC50 about the same as that of PGD2, whereas Δ12-PGJ2 is slightly less potent. Eosinophils pretreated with PGD2 no longer respond to 15d-PGJ2, and vice versa, but in both cases the cells still respond to another eicosanoid proinflammatory mediator, 5-oxo-6,8,11,14-eicosatetraenoic acid. This indicates that the effects of 15d-PGJ2 are mediated by the DP2/chemoattractant receptor-homologous molecule expressed on Th2 cells that has recently been identified in eosinophils. 15d-PGJ2 is selective for the DP2 receptor, in that it has no effect on DP1 receptor-mediated adenylyl cyclase activity in platelets. We conclude that 15d-PGJ2 and 15d-PGD2 are selective DP2 receptor agonists that activate human eosinophils with potencies at least 100 times greater than those for the proposed anti-inflammatory effects of 15d-PGJ2 on other cells.