Role of Kupffer cells in the induction of tolerance of orthotopic liver transplantation in rats.
Because the role of Kupffer cells (KCs) in liver transplantation (LT) tolerance is not well understood, we investigated their role in liver allograft acceptance in rats. Male Sprague-Dawley rats were randomly assigned to either an LT group or a transplantation group pretreated with GdCl(3) (Gd group). The rats were postoperatively sacrificed at indicated times for histology and assessment of KC function, nuclear factor kappa B (NF-kappaB) activity, and cytokine production. KCs and T cells (TCs) were isolated from allografts to assess Fas/Fas ligand (FasL) expression. Cytotoxicity of KCs against TCs was monitored by coculturing of (3)H-thymidine TCs with KCs at various effector-to-target ratios. The results were as follows. First, grafts were spontaneously accepted in the LT group with evident apoptosis of TCs; however, inhibition of KCs by pretreatment with GdCl(3) decreased TC apoptosis and shortened the survival of allografts. Second, KCs in the LT group had increased levels of FasL messenger RNA and protein with respect to that in the Gd group. Third, by in vitro cocultivation assays, KCs induced TC apoptosis though elevated expression of FasL, and this process could be blocked by anti-FasL antibody. Fourth, there was a positive correlation between activation of NF-kappaB and FasL expression in KCs and interleukin-4 production in the LT group, and the activation of NF-kappaB was inhibited by pretreatment with GdCl(3). In conclusion, KC-induced depletion of TCs via the Fas/FasL pathway might play a critical role in LT tolerance. However, the tolerance is abrogated by suppression of FasL and IL-4 expression via inhibition of NF-kappaB activity by GdCl(3).
Chen
Yong
Y
Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, Second Affiliated Hospital, Chongqing University of Medical Sciences, Chongqing, People's Republic of China.
Liu
Zuojin
Z
Liang
Shaoyong
S
Luan
Xiaofeng
X
Long
Feiwu
F
Chen
Jie
J
Peng
Yong
Y
Yan
Lünan
L
Gong
Jianping
J
D000818:Animals; D017209:Apoptosis; D053222:Fas Ligand Protein / Q000378:metabolism; D007108:Immune Tolerance; D015847:Interleukin-4 / Q000378:metabolism; D007728:Kupffer Cells / Q000166:cytology* / Q000502:physiology*; D016031:Liver Transplantation / Q000379:methods*; D008297:Male; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D010587:Phagocytosis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019014:fas Receptor / Q000378:metabolism
D053222:Fas Ligand Protein; D016328:NF-kappa B; D012333:RNA, Messenger; D019014:fas Receptor; D015847:Interleukin-4