Treatment of hepatocytes with transforming growth factor beta 1 (TGF-b
eta 1) induces growth arrest, which is followed by extensive cell deat
h by apoptosis, Previously, we found that TGF-beta 1 down-modulates nu
clear factor (NF)-kappa B/Rel activity in murine B cell lymphomas, ind
ucing apoptosis. Furthermore, p65 (RelA)-deficient mice died during ge
station due to apoptosis of liver cells, Here we have explored the eff
ects of TGF-beta 1 on hepatocytes, using two untransformed murine hepa
tocyte cell lines, AML-12 and NMH, which constitutively express classi
cal NF-kappa B, TGF-beta 1 treatment caused increased NF-kappa B bindi
ng that was followed by a dramatic decrease in NF-kappa B levels that
preceded apoptosis, Ectopic c-Rel expression ablated apoptosis induced
by TGF-beta 1. The down-regulation in NF-kappa B activity correlated
with elevated I kappa B-alpha expression due to hypophosphorylation an
d increased I kappa B-alpha protein stability, Thus, NF-kappa B factor
expression acts directly to promote liver cell survival, Furthermore,
these findings characterize a novel signaling pathway for TGF-beta 1
in epithelial cells involving down-regulation of NF-kappa B/Rel factor
s activity through posttranslational modification of I kappa B-alpha p
rotein.