Graft tumor necrosis factor receptor-1 protects after mouse liver transplantation whereas host tumor necrosis factor receptor-1 promotes injury.

Abstract

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.

CONCLUSION:

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.

• Authors: Lars O Conzelmann, Mark Lehnert, Michael Kremer, Zhi Zhong, Michael D Wheeler, John J Lemasters
• Journal: Transplantation (Transplantation) Vol. 82 Issue 9 Pg. 1214-20 (Nov 15 2006) ISSN: 0041-1337 [Print] United States
• PMID: 17102774 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Tumor Necrosis Factor, Type I
• Alanine Transaminase
• Caspase 3

Topics

• Alanine Transaminase (blood)
• Animals
• Caspase 3 (analysis, metabolism)
• Graft Rejection (genetics, immunology, pathology)
• Liver (enzymology, immunology)
• Liver Transplantation
• Male
• Mice
• Mice, Mutant Strains
• Neutrophil Infiltration
• Receptors, Tumor Necrosis Factor, Type I (genetics, physiology)