Document Detail

Digoxin attenuates acute cardiac allograft rejection by antagonizing RORγt activity.
MedLine Citation:
PMID:  23296151     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Th17 responses have been suggested to participate in the pathogenesis of acute allograft rejection. RORγt is the master transcription factor that controls Th17 cell differentiation and expansion. However, little is known about the effect that antagonizing RORγt activity may have on acute cardiac allograft rejection.
METHODS: A model of heterotopic murine cardiac transplantation with total allomismatch (BALB/c to B6 mice) was used. Digoxin, which was recently identified as a specific antagonist of RORγt, was injected intraperitoneally daily (40 μg) starting 1 day after cardiac transplantation. The severity of rejection was determined by histology. The mRNA expression levels of cytokines and transcription factors in the grafts were measured by quantitative real-time PCR. The proportion and number of T-cell subpopulations in the allografts and spleens were analyzed by flow cytometry. In vitro, the effect of digoxin on allogeneic responses and the interleukin (IL)-6-mediated conversion of regulatory T cells (Treg) into Th17 cells were investigated.
RESULTS: Treatment with digoxin significantly prolonged cardiac allograft survival compared with dimethyl sulfoxide treatment (mean survival time, 16.5±2.2 versus 8.1±0.7 days; P<0.01). Treatment with digoxin also markedly suppressed the mRNA expression levels of IL-17A, IL-17F, and granulocyte-macrophage colony-stimulating factor, reduced the number of Th17 cells, and induced Treg expansion in the allografts. In vitro, treatment with digoxin did not inhibit the proliferation of T cells in a mixed lymphocyte reaction, but it did inhibit the IL-6-mediated conversion of Tregs into Th17 cells.
CONCLUSIONS: RORγt may be a promising therapeutic target to attenuate acute cardiac allograft rejection. Digoxin therefore provides a molecular basis for the design of novel immunosuppressive agents.
Jie Wu; Cheng Zhou; Wenhao Chen; Aini Xie; Jun Li; Sihua Wang; Ping Ye; Wenshuo Wang; Jiahong Xia
Publication Detail:
Type:  Comparative Study; In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Transplantation     Volume:  95     ISSN:  1534-6080     ISO Abbreviation:  Transplantation     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-06     Completed Date:  2013-06-20     Revised Date:  2013-10-27    
Medline Journal Info:
Nlm Unique ID:  0132144     Medline TA:  Transplantation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  434-41     Citation Subset:  IM    
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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MeSH Terms
Cardiotoxins / pharmacology,  therapeutic use
Cell Differentiation / drug effects
Digoxin / pharmacology*,  therapeutic use*
Dimethyl Sulfoxide / pharmacology,  therapeutic use
Graft Rejection / pathology,  prevention & control*
Heart Transplantation* / pathology
Mice, Inbred BALB C
Mice, Inbred C57BL
Models, Animal
Nuclear Receptor Subfamily 1, Group F, Member 3 / antagonists & inhibitors*,  drug effects*
T-Lymphocytes, Regulatory / drug effects,  pathology
Th17 Cells / drug effects,  pathology
Transplantation, Heterotopic
Transplantation, Homologous
Reg. No./Substance:
0/Cardiotoxins; 0/Nuclear Receptor Subfamily 1, Group F, Member 3; 20830-75-5/Digoxin; 67-68-5/Dimethyl Sulfoxide
Erratum In:
Transplantation. 2013 Aug 27;96(4):e33

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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