Tumor necrosis factor induces DNA replication in hepatic cells through nuclear factor kappa B activation

Tumor necrosis factor (TNF) signaling through TNF receptor 1 (TNFR1) with d ownstream participation of nuclear factor kappa B (NF kappa B), interleukin 6 (IL-6), and signal transducers and activators of transcription 3 (STAT3) is required for initiation of liver regeneration. It is not known whether the proliferative effect of TNF on hepatocytes is direct or requires the pa rticipation of Kupffer cells, the liver resident macrophages. Moreover, it has not been determined whether NF kappa B activation is an essential step in TNF-induced proliferation. To answer these questions, we conducted studi es in LE6 cells, a rat liver epithelial cell line with hepatocyte progenito r capacity. We report that TNF induces DNA replication in growth-arrested L E6 cells and that its effect involves the activation of NF kappa B and STAT 3 and an increase in c-myc and IL-6 mRNAs, All of these effects, which mimi c the events that initiate liver regeneration in vivo, are blocked if NF ka ppa B activation is inhibited by expression of a dominant-inhibitor I kappa B alpha mutant (Delta N-I kappa B alpha). Although NF kappa B blockage by Delta N-I kappa B alpha causes caspase activation and massive death of cell s stimulated by TNF, inhibition of NF kappa B and STAT3 binding by the seri ne protease inhibitor N-tosyl-L-phenylalanine chloromethyl ketone results i n G(0)-G(1) cell cycle arrest without death. We conclude that NF kappa B is an essential component of the TNF proliferative pathway and that TNF-induc ed changes in IL-6 mRNA, STAT3, and c-myc mRNA are dependent on NF kappa B activation. Blockage of NF kappa B inhibits TNF-induced proliferation but d oes not necessarily cause cell death.