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Hepatic Tumor Necrosis Factor Signaling and Nuclear Factor-B: Effects on Liver Homeostasis and Beyond

Unit of Molecular Signal Transduction in Inflammation, Department for Molecular Biomedical Research-VIB, and Department of Molecular Biology, Ghent University, Technologiepark 927, B-9052 Ghent (Zwijnaarde), Belgium

Correspondence: Address all correspondence and requests for reprints to: Rudi Beyaert, Department for Molecular Biomedical Research, VIB, Ghent University, Technologiepark 927, B-9052 Ghent (Zwijnaarde), Belgium. E-mail: rudi.beyaert{at}dmbr.ugent.be

The proinflammatory cytokine TNF has a pivotal role in liver pathophysiology because it holds the capacity to induce both hepatocyte cell death and hepatocyte proliferation. This dual effect of TNF on hepatocytes reflects its ability to induce both nuclear factor B (NF-B)-dependent gene expression and cell death. Multiple studies have demonstrated the crucial role of the transcription factor NF-B in the decision between life and death of a hepatocyte. Massive hepatocyte apoptosis preceding embryonic lethality in NF-B-deficient mice constituted the first indication of an essential antiapoptotic function of NF-B in the liver. Although many studies confirmed this crucial cytoprotective role of NF-B in adult liver, a number of genetic studies recently obtained conflicting results on the exact role of NF-B in different mouse models of TNF hepatotoxicity, demonstrating that caution should be taken when interpreting studies using different NF-B-deficient mice in distinct models of liver injury. Recent reports showing a role for hepatic NF-B activation in the proliferation of malignant cells during hepatocarcinogenesis, and in the progression of fatty liver diseases to insulin resistance and type 2 diabetes mellitus demonstrate that NF-B can also have more detrimental effects in the liver. Moreover, its role in the development of the metabolic syndrome emphasizes that hepatic NF-B activation might also have adverse effects on the endocrine system. Therefore, understanding the regulation of hepatic TNF signaling and NF-B activation is of critical therapeutic importance. In this review, we summarize how studies on the role of NF-B in different mouse models of liver pathologies have contributed to this understanding.

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