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15-Deoxy-^12,1412,14-prostaglandins D₂ and J₂ Are Potent Activators of Human Eosinophils¹

Guillaume Monneret^2,*, Hongping Li^*, Julian Vasilescu^*, Joshua Rokach and William S. Powell^3,*

^* Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada; and Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, Melbourne, FL 32901

15-Deoxy-^12,14-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-. 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-^12,14-prostaglandin D₂ (15d-PGD₂) is also a potent activator of eosinophils, with an EC₅₀ about the same as that of PGD₂, whereas ¹²-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.

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