Normal liver regeneration in p50/nuclear factor kappa B1 knockout mice

Nuclear factor kappaB (NF-kappaB) is rapidly activated during liver regener ation following partial hepatectomy or carbon tetrachloride (CCl4)-mediated liver injury and is felt to be important in the antiapoptotic and regenera tive responses. After partial hepatectomy, livers of mice deficient in the p50 subunit of NF-kappaB (p50(-/-)) showed a loss of NF-kappaB and decrease d STAT3 transcription factor DNA binding activities. However, nuclear level s of the NF-kappaB p65 subunit were increased and peaked earlier in p50(-/- ) livers. Both messenger RNA and cytoplasmic protein levels of the NF-kappa B inhibitor I kappaB alpha were lower in p50(-/-) livers, potentially accou nting for the increase in p65 protein. Small effects on gene expression pos thepatectomy were observed in p50-/- livers, but no effects were seen on he patocyte DNA synthetic or mitotic responses, serum enzyme levels, or overal l liver mass restoration. After CCl4 treatment, hepatocyte DNA synthesis an d mitosis and serum enzyme levels were similar in p50(-/-) and p50(+/+) mic e, and histologic analysis indicated a slight decrease in overall damage in p50(-/-) livers. After injection of Fas antibody, p50(-/-) livers showed a n earlier onset of nuclear changes consistent with apoptosis. These data in dicate that absence of p50 affects certain protein and gene activation path ways following partial hepatectomy, CCl4, and Fas treatment but does not im pair overall liver regeneration. Interleukin 6 (IL-6) levels were reduced b ut still adequate to support regeneration. We hypothesize that increased le vels of the NF-kappaB p65 subunit in p50(-/-) livers may provide compensati on for the absence of p50, thereby allowing normal liver regeneration and r epair following liver injury.