Graft tumor necrosis factor receptor-1 protects after mouse liver transplantation whereas host tumor necrosis factor receptor-1 promotes injury.
BACKGROUND
Tumor necrosis factor (TNF)-alpha is a cytokine with pleiotropic effects on the liver. The predominant hepatic receptor for TNFalpha is TNF receptor-1 (TNFR1). TNFR1 mediates liver injury after ischemia/reperfusion but is also mitogenic during hepatic regeneration. This study investigated the role of graft and host TNFR1 in early graft injury after liver transplantation in mice.


METHODS
Livers from TNFR1 deficient (TNFR1-/-) and wild type (WT) mice were transplanted into either TNFR1-/- or WT recipients in all four possible combinations after 12 hours of cold storage. After eight hours, alanine transferase (ALT), necrosis, TdT-mediated dUTP-digoxigenin nick-end labeling (TUNEL) staining, caspase-3 activation, and myeloperoxidase were determined.


RESULTS
When TNFR1-/- livers were transplanted into either WT or TNFR1-/- recipients, ALT was twofold greater than when WT donor livers were used. Necrosis and TUNEL staining also increased twofold and sevenfold, respectively, after transplantation of TNFR1-/- donor livers compared to WT. By contrast, ALT and necrosis decreased when WT or TNFR1-/- livers were transplanted into TNFR1-/- hosts compared to WT, which was associated with decreased neutrophil infiltration.


CONCLUSIONS
In conclusion, graft and recipient TNFR1 has opposing effects. Graft TNFR1 decreases graft injury, whereas recipient TNFR1 mediates an increase of injury associated with enhanced neutrophil infiltration. Cross-transplanting of knockout and wild-type livers provides a new means to investigate graft-host interactions during hepatic injury.
Conzelmann
Lars O
LO
Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, and Department of Trauma, Hand and Reconstructive Surgery, Hospitals of the J.W. Goethe University, Frankfurt, Germany.
Lehnert
Mark
M
Kremer
Michael
M
Zhong
Zhi
Z
Wheeler
Michael D
MD
Lemasters
John J
JJ
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D053148:Caspase 3 / Q000032:analysis / Q000378:metabolism; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008099:Liver / Q000201:enzymology / Q000276:immunology; D016031:Liver Transplantation; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D020556:Neutrophil Infiltration; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000502:physiology*
D047888:Receptors, Tumor Necrosis Factor, Type I; D000410:Alanine Transaminase; D053148:Caspase 3