Data published to date suggest that the 17-kd secreted TNF-α (and not the 26-kd cell-associated form) is primarily responsible for mortality in endotoxin- or bacteremia-induced shock. Studies conducted in the baboon further suggest that these 17-kd TNF-α actions occur principally through p55 signaling.67 However, in 2 recent reports,78,79 data from our laboratory demonstrated that blocking the secreted form of TNF-α with a matrix metalloproteinase inhibitor improves survival to lipopolysaccharide plus D-galactosamine–induced shock in the mouse, but does not protect against the accompanying liver injury. In concanavalin A (conA)-induced hepatitis, matrix metalloproteinase inhibitors actually exacerbate hepatocellular necrosis and apoptosis despite greater than 90% reduction in plasma TNF-α concentrations (Table). Interestingly, treatment with the matrix metalloproteinase inhibitor had a minimal effect on the concentration of membrane-associated TNF-α in the livers of animals with hepatitis. In contrast, a TNF-α binding protein,80 which neutralized both membrane-associated and soluble TNF-α, attenuated both lipopolysaccharide plus D-galactosamine and conA-induced hepatitis in the presence or absence of a matrix metalloproteinase inhibitor. These results suggest that 26-kd cell-associated TNF-α, and not the 17-kd secreted form, plays a critical role in the hepatocellular necrosis and apoptosis that accompany lipopolysaccharide plus D-galactosamine or conA-induced hepatitis. Therefore, the sole blockade of soluble TNF-α may be ineffective in preventing this type of injury. Similarly, Georgopolous et al81 recently demonstrated, using a novel transgenic mouse, that expression of the transmembrane form of TNF-α was adequate to produce experimentally induced arthritis.