Tumor necrosis factor α in the pathogenesis of human and murine fulminant hepatic failure

Abstract

Background & Aims: The tumor necrosis factor (TNF)-α/TNF receptor system is critical for liver development because hepatocytes undergo apoptosis if the antiapoptotic cascades resulting in RelA NF-κB activation are not effective. Therefore, we studied the role of TNF-α in fulminant hepatic failure (FHF) and developed a new therapeutic strategy. Methods: Serum levels and hepatic expression of TNF-α and both TNF receptors were determined by enzyme-linked immunosorbent assay and immunohistochemistry. Adenoviral vectors were constructed expressing dominant-negative proteins interfering with intracellular TNF-α–dependent pathways. The relevance of these constructs was studied in primary mouse hepatocytes and in a murine model of FHF. Results: Serum levels of TNF-α and TNF receptors are significantly increased in FHF; this increase correlates with patient prognosis. In livers of patients with FHF, infiltrating mononuclear cells express high amounts of TNF-α and hepatocytes overexpress TNF receptor 1 (TNF-R1). Apoptotic hepatocytes are significantly increased in FHF, and there is a strong correlation with TNF-α expression, which is even more pronounced in areas of mononuclear infiltrates. In an in vivo FHF model, the Fas-associated death domain (FADD), adenovirus selectively blocked the intracellular pathway, leading to mitochondrial cytochrome c release, caspase-3 activation, and, thus, apoptosis of hepatocytes. Conclusions: The results show that the TNF-α/TNF-R1 system is involved in the pathogenesis of FHF in humans. Studies in this animal model indicate that FADD may serve as a molecular target to prevent liver cell death in vivo.GASTROENTEROLOGY 2000;119:446-460