Prostaglandin E2 receptors EP2 and EP4 are down-regulated in human mononuclear cells after injury

Abstract

Background. Recent characterization of prostaglandin receptor subtypes shows that each is critical to cellular functions and operates through separate signaling pathways that may explain differing effects of prostanoids. This study aimed to determine whether prostaglandin receptors EP2 and EP4 are modulated after injury and to evaluate the effect of prostaglandin E2 (PGE2) addition and blockade on EP receptor expression. Methods. Peripheral blood mononuclear cells (PBMCs) isolated from 10 patients sustaining fracture or burn injury and 10 control subjects were stimulated with lipopolysaccharide ± NS-398, an inhibitor of PGE2 production. Samples were evaluated for production of PGE2, tumor necrosis factor-α, and leukotriene B4 as well as mRNA expression of EP receptors and COX-2. EP receptor expression was also evaluated after treating control PBMCs with PGE2. Results. PBMCs from injured patients exhibited significant increases in PGE2 production and COX-2 mRNA compared with control subjects, and these increases were inhibited by NS-398. In contrast, EP2 and EP4 receptors were markedly down-regulated after injury and NS-398 restored expression to control levels. Decreased EP2 and EP4 receptor expression after injury was replicated by coincubation of PBMCs with PGE2. Conclusions. Specific PGE2 receptors are down-regulated after injury and NS-398 reverses this response. Furthermore, PGE2 mediates EP2 and EP4 down-regulation. These data suggest that specific EP receptor subtypes may provide critical targets for augmenting the immune response after injury in humans. (Surgery 2001;130:249-55.)