NUCLEAR FACTOR-KAPPA-B REL BLOCKS TRANSFORMING-GROWTH-FACTOR BETA-1-INDUCED APOPTOSIS OF MURINE HEPATOCYTE CELL-LINES

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.