The mechanism of anti-inflammatory effects of prostaglandin E2 receptor 4 activation in murine cardiac transplantation.
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.
Ogawa
Masahito
M
Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
Suzuki
Jun-ichi
J
Kosuge
Hisanori
H
Takayama
Kiyoshi
K
Nagai
Ryozo
R
Isobe
Mitsuaki
M
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
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