Nuclear Factor κB Up-Regulation of CCAAT/Enhancer-Binding Protein β Mediates Hepatocyte Resistance to Tumor Necrosis Factor α Toxicity

The sensitization of hepatocytes to cell death from tumor necrosis factor alpha (TNF alpha) underlies many forms of hepatic injury, including that from toxins Critical for hepatocyte resistance to TNF alpha toxicity is activation of nuclear factor kappa B (NF-kappa B) signaling, which prevents TNF alpha-induced death by the up-regulation of protective proteins To further define the mechanisms of hepatocyte sensitization to TNF alpha killing, immunoblot analysis comparing livers from mice treated with lipopolysaccharide (LPS) alone or LPS together with the hepatotoxin galactosamine (GalN) was performed to identify TNF alpha-induced protective proteins blocked by GalN Levels of CCAAT/enhancer-binding protein beta (C/EBP beta) were increased after LPS treatment but not GalN/LPS treatment In a nontransformed rat hepatocyte cell line, TNF alpha-induced increases in C/EBP beta protein levels were dependent on NF beta B mediated inhibition of proteasomal degradation Pharmacological inhibition of c-Jun N-terminal kinase (JNK) did not affect C/EBP beta degradation, indicating that the process was JNK-independent C/EBP beta functioned to prevent cell death as adenoviral C/EBP beta overexpression blocked TNF alpha-induced apoptosis in cells sensitized to TNF alpha toxicity by NF-kappa B inhibition C/EBP beta Inhibited TNF alpha-induced caspase 8 activation and downstream mitochondrial cytochrome c release and caspase 3 and caspase 7 activation Studies in primary hepatocytes from clebp beta(-/-) mice confirmed that loss of C/EBP beta increased death from TNF alpha. clebp beta(-/-) mice were also sensitized to liver injury from a nontoxic dose of LPS or TNF alpha. The absence of jnk2 faded to reverse the GalN-induced block in C/EBP beta induction by LPS, again demonstrating that C/EBP beta degradation was JNK-independent Conclusion C/EBP beta is up-regulated by TNF alpha and mediates hepatocyte resistance to TNF alpha toxicity by inhibiting caspase-dependent apoptosis In the absence of NF-kappa B signaling, proteasomal degradation of C/EBP beta is increased by a JNK-independent mechanism and promotes death from TNF alpha. (HEPATOLOGY 2010,52 2118-2126)