Involvement of prostaglandin receptors (EPR2-4) in in vivo immunosuppression of PGE2 in rat skin transplant model

Background: Prostaglandin E2 (PGE2) is known to modulate immune responses and is widely viewed as a general immunosuppressant. There have been recognized four receptors for PGE2 (EP1-EP4 receptor) so far, and EP2 and EP4 receptors are mainly involved in the immunosuppressive effect of PGE2 in vitro. In the present study we examined the in vivo immunosuppressive effects of selective EP receptor agonists using a high-responder rat skin transplantation model. Materials and methods: Skin allografts from ACI donors were transplanted onto LEW recipients. Agents were injected everyday between day 0 and day 5 after skin transplantation at the dose of 300 μg/kg subcutaneously. Survival of the skin allograft, histological changes and changes of the intragraft cytokine expressions were analyzed using the reverse transcription polymerase chain reaction (RT-PCR). We also assessed the mixed lymphocyte reaction (MLR) assay using splenocytes. Results: PGE2 significantly prolonged allograft survival (18.8 ± 1.5 days) compared with untreated control (14.8 ± 0.8 days). EP2R + EP3R + EP4R agonists also prolonged allograft survival (18.0 ± 1.0 days) although EP3R agonist or EP2R + EP4R agonists alone failed (15.5 ± 0.7, 15.4 ± 1.3 days, respectively). RT-PCR analysis in the skin grafts demonstrated IL-10 up-regulation and IFN-γ down-regulation in all groups except untreated control and EP2R agonist-treated groups. MLR was significantly reduced in groups of EP2R + EP4R agonists, EP2R + EP3R + EP4R agonists and PGE2, compared with untreated control. Conclusions: The effect of PGE2 to prolong the survival of skin transplant requires the action of a combination of three receptors, i.e., EP2 + EP3 + EP4.