Suppression of acute rejection by administration of prostaglandin E2 receptor subtype 4 agonist in rat organ transplantation models

Abstract

Background: Prostaglandin E2 (PGE2) receptor subtype 4 (EP4) signaling is known to modulate the inflammation process. Several studies have demonstrated the potential utility of EP4-selective agonists for the management of autoimmune and inflammatory diseases. In the present study, we assessed the immunosuppressive efficacy of a selective EP4 agonist in experimental rat organ transplantation models.

Methods: We continuously injected a selective EP4 agonist (CAY10580) by subcutaneous insertion of infuser pumps into recipient rats that underwent heterotopic heart and small bowel transplantation.

Results: The administration of EP4 agonist significantly delayed cardiac allograft survival and delayed the onset of rejection in both the cardiac and intestinal allografts. Expression of proinflammatory cytokines of interferon-gamma was suppressed by the treatment compared with the vehicle-treated group. Furthermore, the expression of suppressor of cytokine signaling-1, a known intracellular regulation factor of IFN-gamma, was also down-regulated compared with the control group.

Conclusions: These results suggest that selective EP4 agonists represent a novel class of immune-modulator drugs that could be useful for the management of acute allogeneic rejection.

Keywords: Acute rejection; Heart transplantation; Inflammation; Interferon-gamma; Prostaglandin E(2) receptor subtype 4 agonist; Small bowel transplantation.