Involvement of 26-kDa cell-associated TNF-alpha in experimental hepatitis and exacerbation of liver injury with a matrix metalloproteinase inhibitor.

Solorzano CC, Ksontini R, Pruitt JH, Hess PJ, Edwards PD, Kaibara A, Abouhamze A, Auffenberg T, Galardy RE, Vauthey JN, Copeland EM, Edwards CK, Lauwers GY, Clare-Salzler M, MacKay SL, Moldawer LL, Lazarus DD
J Immunol. 1997 158 (1): 414-9

PMID: 8977217

TNF-alpha 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-alpha 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-alpha concentrations. Treatment with GM-6001 also has minimal effect on the concentration of membrane-associated TNF-alpha 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-alpha, prevents D-GalN/LPS- and Con A-induced hepatitis. Our studies suggest that cell-associated TNF-alpha plays a role in the hepatocellular necrosis and apoptosis that accompany D-GalN/LPS- or Con A-induced hepatitis, and that matrix metalloproteinase inhibitors are ineffective in preventing this hepatic injury.

MeSH Terms (14)

Animals Chemical and Drug Induced Liver Injury Concanavalin A Dipeptides Drug Synergism Galactosamine Lipopolysaccharides Liver Metalloendopeptidases Mice Mice, Inbred C57BL Protease Inhibitors Receptors, Tumor Necrosis Factor Tumor Necrosis Factor-alpha

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