Roles of the tacrolimus-dependent transcription factor IRF4 in acute rejection after liver transplantation

Acute rejection is a serious and life-threatening complication of liver transplantation (LTx). Tacrolimus (TAC) is a potent immunosuppressant used in experimental and clinical transplantation. Interferon regulatory factor 4 (IRF4) plays key roles as a transcription factor in the immune response. This study explored the role of IRF4 in acute rejection after LTx using TAC treatment. Here, LTx was performed in DA (RT1(n)) and Lewis (LEW) (RT1(I)) rats. The recipients were immunosuppressed with TAC (1.5 mg/kg/day subcutaneously) or saline. Liver grafts were harvested 1, 3, 5, 7, and 10 days after LTx for histology, immunohistochemistry, western blotting and real-time PCR. Splenic mononuclear cells were activated with different doses of TAC. The nuclear factor of activated T cells (NFAT) signal pathway and CD4+ T subset-related transcription factors were assessed. The results showed that TAC treatment prolonged the survival of liver allografts in recipients, significantly attenuated hepatic tissue injury and improved liver function. IRF4 expression in grafts was down-regulated after TAC treatment. TAC inhibited the expression of IRF4, NFAT, Foxp3 and ROR gamma t in splenic mononuclear cells in vitro. In conclusions, our studies showed that TAC attenuated acute rejection responses after LTx. This attenuation might depend on the TAC NFAT IRF4 signal pathway, which is crucial for the function of T helper subsets (Treg and Th17 cells) in acute rejection after LTx. These findings contribute to our understanding of the immune pharmacological mechanism of TAC to prevent rejection in LTx rats. (C) 2015 Elsevier B.V. All rights reserved.