title: The anti-inflammatory effects of PGE2on human lung macrophages are mediated by the EP4receptor.
abstract: PGE2inhibits cytokine generation from human lung macrophages. However, the EP receptor that mediates this beneficial anti-inflammatory effect of PGE2has not been defined. The aim of this study was to identify the EP receptor by which PGE2inhibits cytokine generation from human lung macrophages. This was determined by using recently developed EP receptor ligands.
  
  
  
  The effects of PGE2and EP-selective agonists on LPS-induced generation of TNF-α and IL-6 from macrophages were evaluated. The effects of EP2-selective (PF-04852946, PF-04418948) and EP4-selective (L-161,982, CJ-042794) receptor antagonists on PGE2responses were studied. The expression of EP receptor subtypes by human lung macrophages was determined by RT-PCR.
  
  
  
  PGE2inhibited LPS-induced and Streptococcus pneumoniae-induced cytokine generation from human lung macrophages. Analysis of mRNA levels indicated that macrophages expressed EP2and EP4receptors. L-902,688 (EP4receptor-selective agonist) was considerably more potent than butaprost (EP2receptor-selective agonist) as an inhibitor of TNF-α generation from macrophages. EP2receptor-selective antagonists had marginal effects on the PGE2inhibition of TNF-α generation, whereas EP4receptor-selective antagonists caused rightward shifts in the PGE2concentration-response curves.
  
  
  
  These studies demonstrate that the EP4receptor is the principal receptor that mediates the anti-inflammatory effects of PGE2on human lung macrophages. This suggests that EP4receptor agonists could be effective anti-inflammatory agents in human lung disease.
authors.affiliation: Academic Unit of Respiratory Medicine, Department of Infection, Immunity and Cardiovascular Disease, The Medical School (Floor L), University of Sheffield, Sheffield, UK.
authors.forename: Sharonjit K
authors.initials: SK
authors.lastname: Gill
authors.affiliation: Academic Unit of Respiratory Medicine, Department of Infection, Immunity and Cardiovascular Disease, The Medical School (Floor L), University of Sheffield, Sheffield, UK.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Academic Unit of Respiratory Medicine, Department of Infection, Immunity and Cardiovascular Disease, The Medical School (Floor L), University of Sheffield, Sheffield, UK.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Kay
authors.affiliation: Academic Unit of Respiratory Medicine, Department of Infection, Immunity and Cardiovascular Disease, The Medical School (Floor L), University of Sheffield, Sheffield, UK.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Bewley
authors.affiliation: Academic Unit of Respiratory Medicine, Department of Infection, Immunity and Cardiovascular Disease, The Medical School (Floor L), University of Sheffield, Sheffield, UK.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Marriott
authors.affiliation: Academic Unit of Respiratory Medicine, Department of Infection, Immunity and Cardiovascular Disease, The Medical School (Floor L), University of Sheffield, Sheffield, UK. p.t.peachell@shef.ac.uk.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Peachell
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D015232:Dinoprostone / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013296:Streptococcus pneumoniae / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015232:Dinoprostone