15-Deoxy-delta 12,14-prostaglandins D2 and J2 are potent activators of human eosinophils.
15-Deoxy-Delta(12,14)-PDJ(2) (15d-PGJ(2)) is a degradation product of PGD(2) 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-gamma. 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-PGJ(2) has an EC(50) of approximately 10 nM, similar to that of its precursor, PGD(2). The concentrations of 15d-PGJ(2) required to activate eosinophils are thus much lower than those required for its anti-inflammatory effects (usually micromolar). 15-Deoxy-Delta(12,14)-prostaglandin D(2) (15d-PGD(2)) is also a potent activator of eosinophils, with an EC(50) about the same as that of PGD(2), whereas Delta(12)-PGJ(2) is slightly less potent. Eosinophils pretreated with PGD(2) no longer respond to 15d-PGJ(2), 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-PGJ(2) are mediated by the DP(2)/chemoattractant receptor-homologous molecule expressed on Th2 cells that has recently been identified in eosinophils. 15d-PGJ(2) is selective for the DP(2) receptor, in that it has no effect on DP(1) receptor-mediated adenylyl cyclase activity in platelets. We conclude that 15d-PGJ(2) and 15d-PGD(2) are selective DP(2) receptor agonists that activate human eosinophils with potencies at least 100 times greater than those for the proposed anti-inflammatory effects of 15d-PGJ(2) on other cells.
Monneret
Guillaume
G
Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.
Li
Hongping
H
Vasilescu
Julian
J
Rokach
Joshua
J
Powell
William S
WS
D000199:Actins / Q000378:metabolism; D001095:Arachidonic Acids / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000276:immunology; D000242:Cyclic AMP / Q000378:metabolism; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D011108:Polymers / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin / Q000378:metabolism
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000199:Actins; D001095:Arachidonic Acids; D016177:Macrophage-1 Antigen; D011108:Polymers; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C080828:5-oxo-6,8,11,14-eicosatetraenoic acid; D000242:Cyclic AMP; D015230:Prostaglandin D2; D002118:Calcium; C036293:prostaglandin D2 receptor