Rapid DNA binding by nuclear factor kappa B in hepatocytes at the start of liver regeneration

Abstract

Liver regeneration after two-thirds partial hepatectomy (PH) is a process in which quiescent, fully differentiated hepatocytes rapidly reenter the cell cycle and eventually divide until the original liver mass is restored. Although the exact nature of the growth-initiating signals is unknown, enhanced expression of growth-related genes has been detected during the first hour after operation. This suggests that activation of transcriptional and posttranscriptional regulatory factors is likely to be a very early event in liver regeneration. Here we report the rapid, transient induction of DNA binding by nuclear factor (NF)-kappa B (p50/p65 heterodimer) and p50 homodimers within 30 min after PH. We also detected binding of post-hepatectomy factor. NF-kappa B binding peaks at 1 h after PH before declining and is not induced by sham operation. Liver cell separation studies indicated that the binding activation occurs in hepatocytes, a conclusion further supported by cell culture studies using the hepatocyte cell line AML-12. Furthermore, studies with the liver epithelial cell line LE-6 indicated that these DNA-binding activities are mitogen inducible. One-third hepatectomy, a procedure which primes hepatocytes to respond to growth factors, also induced NF-kappa B binding. We also found that tumor necrosis factor alpha, which may be involved in the control of liver regeneration, rapidly induced NF-kappa B DNA-binding activities in intact animals, similar to those induced by PH. These results suggest that NF-kappa B binding may play a role in making hepatocytes competent to proliferate.