Kupffer cell-dependent TNF-α signaling mediates injury in the arterialized small-for-size liver transplantation in the mouse

• DOI: 10.1073/pnas.0600499103
• Publication Date: 2006-03-14T01:49:02Z
• Authors: Yinghua Tian; Wolfram Jochum; Panco Georgiev; Wolfgang Moritz; Rolf Graf; Pierre-Alain Clavien
• Keywords: Male; 0301 basic medicine; 1000 Multidisciplinary; Interleukin-6; Kupffer Cells; Tumor Necrosis Factor-alpha; Graft Survival; 610 Medicine & health; Gadolinium; Arteries; Mice, Mutant Strains; Interleukin-10; Liver Transplantation; 3. Good health; Mice; 03 medical and health sciences; Liver; 10049 Institute of Pathology and Molecular Pathology; Reperfusion Injury; Animals; Regeneration; Pentoxifylline; Signal Transduction

Implantation of small liver grafts causes liver injury and defective regeneration leading to graft failure. We investigated whether Kupffer cell-dependent TNF-α signaling contributes to this poor outcome. Partial 30% liver transplantation was performed in C57BL/6 wild-type mice (control group), and in three groups with down-regulation of the TNF-α pathway: ( i ) TNF receptor 1 knockout [TNFR-1(−/−)] mice, and mice pretreated with ( ii ) gadolinium chloride or ( iii ) pentoxifylline (PTX). Fifty-percent partial liver transplantation, a model associated with full recovery, and transplantation in IL-6 knockout [IL-6(−/−)] mice were performed in some experiments. Graft injury, regeneration, portal flow, liver microcirculation, leukocyte adhesion, and animal survival were assessed. Animal survival rates were 14% in the control group vs. 43% in the gadolinium chloride group, 57% for the TNFR-1(−/−) group, and 86% in the PTX group ( P < 0.001). Markers of liver injury were reduced in all treated groups when compared with controls. Each treated group disclosed better portal flow and sinusoid perfusion, decreased leukocyte adherence, particularly in the PTX group. Liver regeneration occurred only in the treated groups. IL-6 and IL-10 levels were dramatically up-regulated (50×) in the PTX group, and at lower levels in other experimental groups. The protective effect of PTX was lost in IL-6(−/−) mice and protection was restored by a single dose of r-IL-6. In conclusion, interruption of TNF-α signaling or depletion of Kupffer cells improves survival after 30% liver transplantation, reduces liver injury, and enhances regeneration. The superior effects of PTX are mediated by IL-6.