Activation of nuclear factor-κB during orthotopic liver transplantation in rats is protective and does not require kupffer cells

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Abstract
Reperfusion after liver transplantation results in the induction of tumor necrosis factor-α (TNFα) as well as activation of the stress-associated signaling proteins, c-JunN-terminal kinase (JNK), activating protein-1 (AP-1), and nuclear factor-κB (NF-κB). To test the hypothesis that Kupffer cells are involved in the activation of signal transduction cascades during rat liver transplantation, Kupffer cells were depleted from donor liver using gadolinium chloride (GdCl3), and then the activation of JNK, AP-1, and NF-κB were assessed after transplantation. The results showed that GdCl3 treatment did not inhibit the activation of these stress signals, although transplanted livers were depleted of Kupffer cells and partially protected from reperfusion injury. Interleukin-6 (IL-6) and IL-10 messenger RNAs (mRNAs) were induced by transplantation, and the induction was suppressed by Kupffer cell depletion. The induction of TNFα mRNA and serum protein during liver transplantation was unaffected by GdCl3. These results show that Kupffer cells are not a major source of TNFα production after liver transplantation and that stress-signaling protein activation occurs independently of Kupffer cells. Transplantation strongly activates the transcription factor NF-κB, which blocks TNFα-mediated apoptosis in hepatocytes in vitro. To assess the role of NF-κB activation during liver transplantation, the IκBα superrepressor was expressed in donor livers using adenoviral-mediated gene transfer. Inhibition of NF-κB resulted in increased serum alanine aminotransferase levels after 3 hours of transplantation. In addition, the blockade of NF-κB resulted in increased histological tissue injury and increased hepatic terminal deoxyribonucleotide transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining, indicating apoptosis. These results show that NF-κB activation has a protective role in the transplanted liver.