Background: Prostaglandin E2 (PGE2)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 a rat heterotopic small bowel transplantation model.
Methods: Immunosuppressive effects of an EP4-selective agonist of CAY10580 were assessed in Brown Norway (BN) (RT-1n haplotype) to Lewis (RT-1l) rat heterotopic small bowel transplantation model. The Institutional Ethics Committee for Animal Experimentation approved all experiments (F-173/2012). CAY10580 was continuously injected by subcutaneous insertion of infuser pumps into recipient rats between day 0 and day 6 after transplantation. At day 6, the extent of acute rejection of intestinal allografts was evaluated with histological and immunohistochemical examinations, and pro- and anti-inflammatory cytokines expressions were also evaluated by quantitative RT-PCR and ELISA.
Results: The administration of CAY10580 significantly prolonged the viability of epithelial mucosal cell (n =5, 7 ± 3 cells vs 146 ± 22 cells per 0.5-mm square; p < 0.01), and suppressed the infiltration of CD3+ cells in intestinal allografts. Expression of pro-inflammatory cytokines of interferon-Γ (IFN-Γ) in plasma was suppressed by the treatment compared with the vehicle-treated group (n=5, 610.2 ± 80.1 vs 462.1 ± 22.9 pg/ml, p < 0.05). Furthermore, the mRNA expression level of suppressor of cytokine signaling-1 (SOCS-1), a known intracellular regulation factor of IFN-Γ, was also down-regulated compared with the control group.
Conclusions: Those results suggest that EP4-selective agonists delayed the onset of acute rejection in intestinal allografts through the control of SOCS-1-IFN-Γ signaling pathway. EP4-selective agonists could be useful for the management of acute rejection after small bowel transplantation.
To cite this abstract in AMA style:Okamoto T, Tamura R, Okamoto S, Fujimoto Y, Tabata Y, Uemoto S. Suppression of Acute Rejection by Administration of Prostaglandin E2 Receptor Subtype 4 (EP4) Agonist in a Rat Heterotopic Small Bowel Transplantation Model [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/suppression-of-acute-rejection-by-administration-of-prostaglandin-e2-receptor-subtype-4-ep4-agonist-in-a-rat-heterotopic-small-bowel-transplantation-model/. Accessed May 7, 2021.
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