Activation of nuclear factor-κB during orthotopic liver transplantation in rats is protective and does not require kupffer cells
✍ Scribed by Bradham, Cynthia A. ;Schemmer, Peter ;Stachlewitz, Robert F. ;Thurman, Ronald G. ;Brenner, David A.
- Publisher
- Wiley (John Wiley & Sons)
- Year
- 1999
- Tongue
- English
- Weight
- 436 KB
- Volume
- 5
- Category
- Article
- ISSN
- 1074-3022
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✦ Synopsis
Reperfusion after liver transplantation results in the induction of tumor necrosis factor-␣ (TNF␣) as well as activation of the stress-associated signaling proteins, c-Jun N-terminal kinase (JNK), activating protein-1 (AP-1), and nuclear factor-B (NF-B). 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 (GdCl 3 ), and then the activation of JNK, AP-1, and NF-B were assessed after transplantation. The results showed that GdCl 3 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 TNF␣ mRNA and serum protein during liver transplantation was unaffected by GdCl 3 . These results show that Kupffer cells are not a major source of TNF␣ production after liver transplantation and that stress-signaling protein activation occurs independently of Kupffer cells. Transplantation strongly activates the transcription factor NF-B, which blocks TNF␣-mediated apoptosis in hepatocytes in vitro. To assess the role of NF-B activation during liver transplantation, the IB␣ superrepressor was expressed in donor livers using adenoviral-mediated gene transfer. Inhibition of NF-B resulted in increased serum alanine aminotransferase levels after 3 hours of transplantation. In addition, the blockade of NF-B 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-B activation has a protective role in the transplanted liver.