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

I Kirillova, M Chaisson, N Fausto - 1999 - AACR
I Kirillova, M Chaisson, N Fausto
1999AACR
Tumor necrosis factor (TNF) signaling through TNF receptor 1 (TNFR1) with downstream
participation of nuclear factor κB (NFκB), 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 NFκB activation is an essential step in TNF-induced proliferation. To …
Abstract
Tumor necrosis factor (TNF) signaling through TNF receptor 1 (TNFR1) with downstream participation of nuclear factor κB (NFκB), 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 NFκB 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 NFκB 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 NFκB activation is inhibited by expression of a dominant-inhibitor IκBα mutant (ΔN-IκBα). Although NFκB blockage by ΔN-IκBα causes caspase activation and massive death of cells stimulated by TNF, inhibition of NFκB 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 NFκB 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 NFκB activation. Blockage of NFκB inhibits TNF-induced proliferation but does not necessarily cause cell death.
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