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Cell Growth & Differentiation Vol. 10, 819-828, December 1999
© 1999 American Association for Cancer Research

Tumor Necrosis Factor Induces DNA Replication in Hepatic Cells through Nuclear Factor {kappa}B Activation1

Irina Kirillova, Michelle Chaisson and Nelson Fausto2

Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195-7470

Tumor necrosis factor (TNF) signaling through TNF receptor 1 (TNFR1) with downstream 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 participation 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 studies in LE6 cells, a rat liver epithelial cell line with hepatocyte progenitor capacity. We report that TNF induces DNA replication in growth-arrested LE6 cells and that its effect involves the activation of NF{kappa}B and STAT3 and an increase in c-myc and IL-6 mRNAs. All of these effects, which mimic the events that initiate liver regeneration in vivo, are blocked if NF{kappa}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 cells stimulated by TNF, inhibition of NF{kappa}B and STAT3 binding by the serine protease inhibitor N-tosyl-L-phenylalanine chloromethyl ketone results in G0-G1 cell cycle arrest without death. We conclude that NF{kappa}B is an essential component of the TNF proliferative pathway and that TNF-induced 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 does not necessarily cause cell death.




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Molecular Cancer Research Cell Growth & Differentiation
Copyright © 1999 by the American Association of Cancer Research.