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Lethal hepatic apoptosis mediated by tumor necrosis factor receptor, unlike Fas-mediated apoptosis, requires
M Nagaki1, A Sugiyama, Y Osawa
1First Department of Internal Medicine, Gifu University School of Medicine, Japan.
Background/Aims:
Tumor necrosis factor a (TNF-alpha) and Fas ligand are apoptotic cell-death mediators that act by binding to their responsive receptors. The aims of this study were to assess the differences between liver cell deaths induced by TNF-alpha and anti-Fas antibody, and to investigate the mechanism by which GalN sensitizes the hepatocyte to injury by TNF-alpha.
Methods:
TNF-alpha or anti-Fas antibody was injected into BALB/c mice sensitized or unsensitized by D-galactosamine (GalN). Liver injury was assessed biochemically and histologically. The expressions of TNF receptor (TNFR)1 and TNFR2 mRNA in the liver were determined by Northern blot analysis. Nuclear factor-kappaB (NF-kappaB) DNA binding activity was determined by gel shift assay.
Results:
In GalN-sensitized mice, hepatocyte apoptosis and liver failure were observed after TNF-alpha injection, but neither occurred in unsensitized mice. Microscopically, GalN preceding TNF-alpha caused massive hemorrhagic liver damage with fragmented hepatocyte nuclei resembling effects of anti-Fas antibody, but GalN largely failed to sensitize to injury by this antibody. TNFR1 mRNA expression in the liver was upregulated within 3 h after GalN administration, and anti-TNFR1 antibody protected GalN-sensitized mice from hepatotoxic effects of TNF-alpha. GalN treatment failed to affect TNF-alpha-induced NF-kappaB activation.
Conclusions:
Unlike Fas-related apoptosis, TNFR-mediated apoptosis requires hepatocyte sensitization involving TNFR1 upregulation.
Insights
Hepatocyte (liver cell) injury from tumor necrosis factor alpha (TNF-alpha) requires liver cell sensitization via upregulation of its receptor, TNFR1. This sensitization mechanism differs from Fas ligand-induced liver cell death.
Area of Science:
- Hepatology
- Immunology
- Cell Death Mechanisms
Background:
- Tumor necrosis factor alpha (TNF-alpha) and Fas ligand are key mediators of apoptotic cell death.
- Understanding the distinct mechanisms of liver cell death induced by these mediators is crucial for therapeutic development.
Purpose of the Study:
- To compare liver cell death induced by TNF-alpha versus anti-Fas antibody.
- To elucidate how D-galactosamine (GalN) sensitizes hepatocytes to TNF-alpha-induced liver injury.
Main Methods:
- Administered TNF-alpha or anti-Fas antibody to GalN-sensitized and unsensitized mice.
- Assessed liver injury biochemically and histologically.
- Quantified TNF receptor (TNFR)1 and TNFR2 mRNA expression and NF-kappaB activation.
Main Results:
- GalN sensitization led to TNF-alpha-induced hepatocyte apoptosis and liver failure, unlike in unsensitized mice.
- GalN pretreatment upregulated TNFR1 mRNA, and anti-TNFR1 antibody protected against TNF-alpha toxicity.
- GalN did not enhance anti-Fas antibody-induced liver injury or affect TNF-alpha-induced NF-kappaB activation.
Conclusions:
- TNF receptor (TNFR)-mediated apoptosis necessitates hepatocyte sensitization through TNFR1 upregulation.
- This sensitization pathway is distinct from that of Fas ligand-mediated apoptosis.