title: The mechanism of anti-inflammatory effects of prostaglandin E2 receptor 4 activation in murine cardiac transplantation.
abstract: BACKGROUND
  Prostaglandin E2 (PGE2) is a pathogenesis of inflammatory diseases; PGE2 plays a key role in association of anti-inflammation and immune suppression. EP4, which is a PGE2 receptor, is known to suppress the production of inflammatory cytokines and chemokines in vitro. Although it has been reported that EP4 agonists prolonged cardiac allograft survival, little has been elucidated the immunologic mechanism.
  
  
  METHODS
  We injected a selective EP4 agonist (EP4RAG) into recipient mice with heterotopic cardiac transplantation.
  
  
  RESULTS
  EP4RAG significantly prolonged the graft survival compared with the vehicle-treated group. Although the vehicle-treated group showed severe myocardial cell infiltration, the EP4RAG-treated group attenuated the development on day 7. EP4RAG suppressed various proinflammatory factors such as cytokines, chemokines, adhesion molecules, and nuclear factor-kappaB (NF-kappaB) compared with the vehicle-treated group. We also demonstrated that EP4RAG suppressed the activation of macrophages, but it did not affect to T lymphocytes in vitro. EP4RAG inhibited the activation of NF-kappaB compared with the control group.
  
  
  CONCLUSIONS
  Pharmacological selective EP4 activation suppressed the production of proinflammatory factors by inhibition of NF-kappaB activity in cardiac transplantation.
authors.affiliation: Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Ogawa
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Suzuki
authors.forename: Hisanori
authors.initials: H
authors.lastname: Kosuge
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takayama
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Isobe
mesh_terms: D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000517:prevention & control*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D008198:Lymph Nodes / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D016328:NF-kappa B / Q000032:analysis; D016133:Polymerase Chain Reaction; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000187:drug effects / Q000502:physiology*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology / Q000473:pathology
chemical_list: D016328:NF-kappa B; C545651:Ptger4 protein, mouse; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D018799:Intercellular Adhesion Molecule-1; D000527:Alprostadil