Abstract
TNF-α is a pleiotropic cytokine that exists both as a 26-kDa cell-associated and a 17-kDa soluble form. Recently, a class of matrix metalloproteinase inhibitors has been identified that can prevent the processing by TNF convertase of 26-kDa TNF-α to its 17-kDa form and can reduce mortality from normally lethal doses of D-galactosamine plus LPS (D-GalN/LPS). Here we report that a matrix metalloproteinase inhibitor, GM-6001, improves survival but does not protect against liver injury from D-GalN/ LPS-induced shock in the mouse. In Con A-induced hepatitis, GM-6001 actually exacerbates hepatocellular necrosis and apoptosis despite greater than 90% reduction in plasma TNF-α concentrations. Treatment with GM-6001 also has minimal effect on the concentration of membrane-associated TNF-α in the livers of animals with Con A induced hepatitis. In contrast, a TNF binding protein (TNF-bp), which neutralizes both membrane-associated and soluble TNF-α, prevents D-GalN/LPS- and Con A-induced hepatitis. Our studies suggest that cell-associated TNF-α plays a role in the hepatocellular necrosis and apoptosis that accompany D-CalN/LPS- or Con A-induced hepatitis, and that matrix metalloproteinase inhibitors are ineffective in preventing this hepatic injury.
Original language | English (US) |
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Pages (from-to) | 414-419 |
Number of pages | 6 |
Journal | Journal of Immunology |
Volume | 158 |
Issue number | 1 |
State | Published - Jan 1 1997 |
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology