The effects of PDTC plus leflunomide and cyclosporine on the NF-κB signaling pathway in mouse-to-rat cardiac xenografts

Abstract

In this study, the effects of pirrolidine dithiocarbamate (PDTC) plus leflunomide (Lef) and cyclosporine (CsA) on the NF-κB signaling pathway in mouse-to-rat cardiac xeno-transplantation models were investigated. NIH mice and Wistar rats served as donors and recipients respectively. Mouse-to-rat cardiac xenotransplantation was performed. The recipients were divided into 5 groups: group A (the control group), group B (PDTC group), group C (PDTC plus CsA group), group D (PDTC plus Lef group) and group E (PDTC plus Lef and CsA group). The expressions of IKKα/β, NF-κB-P65, IκBα, ICAM-1 and NF-κB DNA binding activity in xenograft tissues were determined by immunohistochemistry and Western blot as well as electrophoretic mobility shift assay (EMSA). The median survival time of cardiac xenografts in the control group, PDTC group, PDTC plus CsA group, PDTC plus Lef group and PDTC plus Lef and CsA group was (2.17±0.41), (2.33±0.52), (4.67±1.21), (7.00±1.79) and (9.00±1.41) days respectively. The survival time of xenografts in the PDTC plus Lef and CsA group was significantly longer than that in other four groups (P<0.05 for all), that in the PDTC plus Lef group longer than that in the control group, PDTC group and PDTC plus CsA group (P<0.05 for all), that in PDTC plus CsA group longer than the control group and PDTC group (P<0.05 for all). The expressions of IKKα/β, NF-κB-P65, IκBα and ICAM-1 and NF-κB DNA binding activity were notably increased in mouse-to-rat cardiac xenografts. The expressions were decreased in the control group, PDTC group, PDTC plus CsA group, PDTC plus Lef and PDTC plus Lef and CsA group in turn. It was concluded that PDTC plus Lef and CsA can significantly suppress the expressions of IKKα/β, NF-κB-P65, IκBα, ICAM-1 and NF-κB DNA binding activity, thereby prolonging the survival of the cardiac xenografts.

Keywords

xenotransplantation / NF-κB / heart transplantation / immunosuppressant / pirrolidine dithiocarbamate

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