title: 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 E(2) (PGE(2)) 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 PGE(2) production. Samples 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 with PGE(2).
  
  
  RESULTS
  PBMCs from injured patients exhibited significant increases in PGE(2) 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 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 down-regulation. These data suggest that specific EP receptor subtypes may provide critical targets for augmenting the immune response after injury in humans.
authors.affiliation: Department of Surgery, New York Presbyterian Hospital-Weill Medical College of Cornell Univerity, New York, NY 10021, USA.
authors.forename: V E
authors.initials: VE
authors.lastname: Strong
authors.forename: J
authors.initials: J
authors.lastname: Winter
authors.forename: Z
authors.initials: Z
authors.lastname: Yan
authors.forename: G P
authors.initials: GP
authors.lastname: Smyth
authors.forename: J R
authors.initials: JR
authors.lastname: Mestre
authors.forename: S
authors.initials: S
authors.lastname: Maddali
authors.forename: P A
authors.initials: PA
authors.lastname: Schaefer
authors.forename: R W
authors.initials: RW
authors.lastname: Yurt
authors.forename: P P
authors.initials: PP
authors.lastname: Stapleton
authors.forename: J M
authors.initials: JM
authors.lastname: Daly
mesh_terms: D000328:Adult; D000368:Aged; D002056:Burns / Q000276:immunology* / Q000378:metabolism; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000032:analysis / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D005260:Female; D050723:Fractures, Bone / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism; D007975:Leukotriene B4 / Q000032:analysis / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D018078:Receptors, Prostaglandin E / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction / Q000276:immunology; D013449:Sulfonamides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009578:Nitrobenzenes; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D007975:Leukotriene B4; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone