Activation of nuclear factor-kappa B during orthotopic liver transplantation in rats is protective and does not require Kupffer cells

Reperfusion after liver transplantation results in the induction of tumor n ecrosis factor-alpha (TNF alpha) as well as activation of the stress-associ ated signaling proteins, c-Jun N-terminal kinase (JNK), activating protein- 1 (AP-1), and nuclear factor-kappa B (NF-kappa B), To test the hypothesis t hat Kupffer cells are involved in the activation of signal transduction cas cades during rat liver transplantation, Kupffer cells were depleted from do nor liver using gadolinium chloride (GdCl3), and then the activation of JNK , AP-1, and NF-kappa B were assessed after transplantation. The results sho wed that GdCl3 treatment did not. inhibit the activation of these stress si gnals, although transplanted livers were depleted of Kupffer cells and part ially protected; from reperfusion injury. Interleukin-6 (IL-6) and IL-10 me ssenger RNAs (mRNAs) were induced by transplantation, and the induction was suppressed by Kupffer cell depletion. The induction of TNF alpha mRNA and serum protein during liver transplantation was unaffected by GdCl3. These r esults show that Kupffer cells are not a major source of TNF alpha producti on after liver transplantation and that stress-signaling protein activation occurs independently of Kupffer cells. Transplantation strongly activates the transcription factor NF-kappa B, which blocks TNF alpha-mediated apopto sis in hepatocytes in vitro. To assess the role of NF kappa B activation du ring liver transplantation; the I kappa B alpha superrepressor was expresse d in donor livers using adenoviral-mediated gene transfer. Inhibition of NF -kappa B resulted in increased serum alanine aminotransferase levels after 3 hours of transplantation. In addition, the blockade of NF-kappa B resulte d in increased histological tissue injury and increased hepatic terminal de oxyribonucleotide transferase-mediated deoxyuridine triphosphate nick end l abeling (TUNEL) staining, indicating apoptosis, These results show that NF- kappa B activation has a protective role in the transplanted liver. Copyrig ht (C) 1999 by the American Association for the Study of Liver Diseases.