Roles Of The Tacrolimus-dependent Transcription Factor IRF4 In Acute Rejection After Liver Transplantation

Background: Liver transplantation(LTx) is the treatment for a variety of liver diseases. 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, which inhibit IL-2 expression through NFAT(nuclear factor of activated T cells) in T lymphocytes. Interferon regulatory factor 4(IRF4) is a transcription factor that is expressed in hematopoietic cells, and it plays pivotal roles in the immune response.Objective: This study aimed to explore the role of IRF4 in acute rejection after LTx using TAC treatment and to understand the immune pharmacological mechanism of TAC in the attenuation of rejection in LTx rats.Methods: LTx was performed in DA(RT1n) and Lewis(LEW)(RT1l) 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.Results: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 also down-regulated IRF4, NFAT, Foxp3 and RORγt in splenic mononuclear cells in vitro.Conclusion: 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 abrogate rejection in LTx rats, as well, these findings suggested that IRF4 be used as a novel drug target(a potent immunosuppressant) for controlling the acute rejection after LTx.