Conzelmann Lars O, Lehnert Mark, Kremer Michael, Zhong Zhi, Wheeler Michael D, Lemasters John J
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.
Transplantation. 2006 Nov 15;82(9):1214-20. doi: 10.1097/01.tp.0000239190.95190.5e.
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.
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.
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.
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.
肿瘤坏死因子（TNF）-α是一种对肝脏具有多效性作用的细胞因子。TNFα在肝脏中的主要受体是TNF受体-1（TNFR1）。TNFR1介导缺血/再灌注后的肝损伤，但在肝再生过程中也具有促有丝分裂作用。本研究调查了移植肝和宿主TNFR1在小鼠肝移植后早期移植肝损伤中的作用。
在冷保存12小时后，将来自TNFR1缺陷（TNFR1-/-）和野生型（WT）小鼠的肝脏以所有四种可能的组合移植到TNFR1-/-或WT受体中。八小时后，测定丙氨酸转氨酶（ALT）、坏死情况、TdT介导的dUTP-地高辛素缺口末端标记（TUNEL）染色、半胱天冬酶-3激活情况和髓过氧化物酶。
当将TNFR1-/-肝脏移植到WT或TNFR1-/-受体中时，ALT比使用WT供体肝脏时高出两倍。与WT相比，移植TNFR1-/-供体肝脏后，坏死和TUNEL染色也分别增加了两倍和七倍。相比之下，当将WT或TNFR1-/-肝脏移植到TNFR1-/-宿主中时，与WT相比，ALT和坏死情况减少，这与中性粒细胞浸润减少有关。
总之，移植肝和受体的TNFR1具有相反的作用。移植肝TNFR1可减少移植肝损伤，而受体TNFR1介导与中性粒细胞浸润增强相关的损伤增加。敲除型和野生型肝脏的交叉移植为研究肝损伤期间的移植-宿主相互作用提供了一种新方法。
