Abstract
Background Aglaia (Meliaceae) species are used for treating autoimmune disorders and allergic diseases in Asian countries. Rocaglamide, an extract obtained from Aglaia species, exhibits suppressive effect by regulating the T cell subset balance and cytokine network in cancer. However, whether it can be used in organ transplantation is unknown. In this study, we investigated the antirejection effect and mechanism of action of rocaglamide in a mouse cardiac allograft model. Methods Survival studies were performed by administering mice with phosphate-buffered saline (PBS) (n = 6) and rocaglamide (n = 8). Heart grafts were monitored until they stopped beating. After grafting, the mice were sacrificed on day 7 for histological, mixed lymphocyte reaction (MLR), enzyme-linked immunosorbent assay (ELISA), and flow cytometric analyses. Results Rocaglamide administration significantly prolonged the median survival of the grafts from 7 to 25 days compared with PBS treatment (P < 0.001). On posttransplantation day 7, the rocaglamide-treated group showed a significant decrease in the percentage of Th1 cells (7.9 ± 0.9% vs. 1.58 ± 0.5%, P < 0.001) in the lymph nodes and spleen (8.0 ± 2.5% vs. 2.4 ± 1.3%, P < 0.05). Rocaglamide treatment also significantly inhibited the production of Th17 cells (6.4 ± 1.0% vs. 1.8 ± 0.4%, P < 0.01) in the lymph nodes and spleen (5.9 ± 0.3% vs. 2.9 ± 0.8%, P < 0.01). Furthermore, the prolonged survival of the grafts was associated with a significant decrease in IFN-γ and IL-17 levels. Our results also showed that NF-AT activation was inhibited by rocaglamide, which also induced p38 and Jun N-terminal kinase (JNK) phosphorylation in Jurkat T cells. Furthermore, by using inhibitors that suppressed p38 and JNK phosphorylation, rocaglamide-mediated reduction in NF-AT protein levels was prevented. Conclusion We identified a new immunoregulatory property of rocaglamide, wherein it was found to regulate oxidative stress response and reduce inflammatory cell infiltration and organ injury, which have been associated with the inhibition of NF-AT activation in T cells.
Highlights
Organ transplantation is an effective therapy for patients with end-stage organ disease [1]
Recipients were treated with rocaglamide (2.5 μg/g in 50 μl phosphate-buffered saline (PBS); ip; n = 8), and the control group was treated with PBS (50 μl PBS; ip; n = 6)
Consistent with the findings of Deng et al and Mandy et al [1, 29], we found that IL-17 produced by T helper 17 cells (Th17) cells may play a key role in allograft rejection and its secretion was prevented by rocaglamide
Summary
Organ transplantation is an effective therapy for patients with end-stage organ disease [1]. Previous studies have focused on developing the optimum function of allografts by using immunosuppressive drugs, which are important for investigating the precise cell-mediated immune response and finding a way to downregulate the specific immunoreaction. These drugs can reduce the secretion and chemotaxis of inflammatory factors and reduce oxidative stress damage and protect the allograft. Rocaglamide, an extract obtained from Aglaia species, exhibits suppressive effect by regulating the T cell subset balance and cytokine network in cancer. Whether it can be used in organ transplantation is unknown. We identified a new immunoregulatory property of rocaglamide, wherein it was found to regulate oxidative stress response and reduce inflammatory cell infiltration and organ injury, which have been associated with the inhibition of NF-AT activation in T cells
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