title: Roles of the tacrolimus-dependent transcription factor IRF4 in acute rejection after liver transplantation.
abstract: 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(l)) rats. The recipients were immunosuppressed with TAC (1.5mg/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 RORγt 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.
authors.affiliation: The Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, China.
authors.forename: Tengqian
authors.initials: T
authors.lastname: Tang
authors.affiliation: The Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Lu
authors.affiliation: The Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, China; The Institute of Hepatobiliary Surgery, 324 Hospital of People's Liberation Army (PLA), China.
authors.forename: Xing
authors.initials: X
authors.lastname: Yang
authors.affiliation: The Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, China.
authors.forename: Xiangde
authors.initials: X
authors.lastname: Liu
authors.affiliation: The Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Liao
authors.affiliation: The Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, China.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, China. Electronic address: yangzy0911@sina.com.
authors.forename: Zhanyu
authors.initials: Z
authors.lastname: Yang
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D006084:Graft Rejection / Q000235:genetics* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D050835:Interferon Regulatory Factors / Q000096:biosynthesis* / Q000187:drug effects; D008099:Liver / Q000473:pathology; D016031:Liver Transplantation; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D009000:Monocytes / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology*; D000099218:Interferon Regulatory Factor-4
chemical_list: D007166:Immunosuppressive Agents; D050835:Interferon Regulatory Factors; D016559:Tacrolimus; D000099218:Interferon Regulatory Factor-4
keywords: IRF4; Liver transplantation; NFAT; Tacrolimus