INVOLVEMENT OF 26-KDA CELL-ASSOCIATED TNF-ALPHA IN EXPERIMENTAL HEPATITIS AND EXACERBATION OF LIVER-INJURY WITH A MATRIX METALLOPROTEINASE INHIBITOR

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 meta lloproteinase inhibitors has been identified that can prevent the proc essing by TNF convertase of 26-kDa TNF-alpha to its 17-kDa form and ca n reduce mortality from normally lethal doses of D-galactosamine plus LPS (D-GalN/LPS). Here we report that a matrix metalloproteinase inhib itor, GM-6001, improves survival but does not protect against liver in jury from D-GalN/LPS-induced shock in the mouse. In Con A-induced hepa titis, GM-6001 actually exacerbates hepatocellular necrosis and apopto sis despite greater than 90% reduction in plasma TNF-alpha concentrati ons. Treatment with GM-6001 also has minimal effect on the concentrati on of membrane-associated TNF-alpha in the livers of animals with Con A induced hepatitis. In contrast, a TNF binding protein (TNF-bp), whic h neutralizes both membrane-associated and soluble TNF-alpha, prevents D-GalN/LPS- and Con A-induced hepatitis. Our studies suggest that cel l-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.