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Nuclear factor-kappaB/Rel blocks transforming growth factor beta1-induced apoptosis of murine hepatocyte cell lines
M Arsura1, M J FitzGerald, N Fausto
1Department of Biochemistry, Boston University School of Medicine, Massachusetts 02118-2394, USA.
Abstract:
Treatment of hepatocytes with transforming growth factor beta1 (TGF-beta1) induces growth arrest, which is followed by extensive cell death by apoptosis. Previously, we found that TGF-beta1 down-modulates nuclear factor (NF)-kappaB/Rel activity in murine B cell lymphomas, inducing apoptosis. Furthermore, p65 (RelA)-deficient mice died during gestation due to apoptosis of liver cells. Here we have explored the effects of TGF-beta1 on hepatocytes, using two untransformed murine hepatocyte cell lines, AML-12 and NMH, which constitutively express classical NF-kappaB. TGF-beta1 treatment caused increased NF-kappaB binding that was followed by a dramatic decrease in NF-kappaB levels that preceded apoptosis. Ectopic c-Rel expression ablated apoptosis induced by TGF-beta1. The down-regulation in NF-kappaB activity correlated with elevated IkappaB-alpha expression due to hypophosphorylation and increased IkappaB-alpha protein stability. Thus, NF-kappaB factor expression acts directly to promote liver cell survival. Furthermore, these findings characterize a novel signaling pathway for TGF-beta1 in epithelial cells involving down-regulation of NF-kappaB/Rel factors activity through posttranslational modification of IkappaB-alpha protein.
Insights
Transforming growth factor beta1 (TGF-beta1) triggers liver cell death by reducing nuclear factor kappa B (NF-kappaB) activity. Restoring NF-kappaB levels prevents this apoptosis, highlighting its role in liver cell survival.
Area of Science:
- Hepatology
- Molecular Biology
- Immunology
Background:
- Transforming growth factor beta1 (TGF-beta1) induces apoptosis in hepatocytes.
- TGF-beta1 down-modulates nuclear factor kappa B (NF-kappaB)/Rel activity, leading to apoptosis in B cell lymphomas.
- NF-kappaB (specifically p65/RelA) is crucial for liver cell survival during development.
Purpose of the Study:
- To investigate the role of NF-kappaB in TGF-beta1-induced apoptosis in hepatocytes.
- To elucidate the signaling pathway by which TGF-beta1 affects NF-kappaB activity in liver cells.
Main Methods:
- Utilized two murine hepatocyte cell lines (AML-12 and NMH) expressing constitutive NF-kappaB.
- Treated cells with TGF-beta1 and analyzed NF-kappaB binding activity, levels, and apoptosis.
- Examined the effect of ectopic c-Rel expression and IkappaB-alpha modifications.
Main Results:
- TGF-beta1 treatment initially increased NF-kappaB binding, followed by a significant decrease preceding apoptosis.
- Ectopic expression of c-Rel inhibited TGF-beta1-induced apoptosis.
- Down-regulation of NF-kappaB activity correlated with increased IkappaB-alpha stability due to hypophosphorylation.
Conclusions:
- NF-kappaB factor expression is essential for promoting liver cell survival.
- TGF-beta1 induces hepatocyte apoptosis by down-regulating NF-kappaB/Rel activity via IkappaB-alpha posttranslational modification.
- Identified a novel TGF-beta1 signaling pathway in epithelial cells involving NF-kappaB regulation.