Prostaglandin E-2 receptors EP2 and EP4 are down-regulated in human mononuclear cells rafter injury

Background. Recent characterization of prostaglandin receptor subtypes show s that each is critical to cellular functions arid operates through separat e signaling pathways that may explain differing effects of prostanoids. Thi s study aimed to determine whether prostaglandin receptors EP2 and EP4 are modulated after injury and to evaluate the effect of prostaglandin E-2 (PGE (2)) addition and blockade on EP receptor expression. Methods. Peripheral blood mononuclear cells (PBMCs) isolated from 10 patien ts sustaining fracture or burn injury and 10 control subjects were stimulat ed with lipopolysaccharide +/- NS-398, an inhibitor of PGE(2) production. S amples were evaluated for production of PGE(2), tumor necrosis factor-alpha , and leukotriene B-4 as well as mRNA expression of EP receptors and COX-2. EP receptor expression was also evaluated after treating control PBMCs wit h PGE(2). Results. PBMCs from injured patients exhibited significant increases in PGE (2) production and COX-2 mRNA compared with control subjects, arid these in creases were inhibited by NS-398. In contrast, EP2 and EP4 receptors were m arkedly down-regulated after injury and NS-398 restored expression to contr ol levels. Decreased EP2 arid EP4 receptor expression after injury was repl icated by coincubation of PBMCs with PGE(2). Conclusions. Specific PGE(2) receptors are down-regulated after injury and NS-398 reverses this response. Furthermore, PGE(2) mediates EP2 and EP4 dow n-regulation. These data suggest that specific EP receptor subtypes may pro vide critical targets for augmenting the immune response after injury in hu mans.