Involvement of tumor necrosis factor-α in the pathogenesis of activated macrophage-mediated hepatitis in mice

The possible involvement of tumor necrosis factor-α in the pathogenesis of an experimentally induced hepatitis was investigated. Balb/c mice were primed with Propionibacterium acnes to induce the infiltration of mononuclear cells into the liver. Immunohistochemical study showed that most of the accumulated mononuclear cells at 7 days were Mac-2 positive, suggesting that they were activated macrophages. An injection of lipopolysaccharide resulted in massive hepatic necrosis and high mortality in the mice within 24 hours. Plasma tumor necrosis factor-α activity initially rose sharply and then declined over 3 hours. The increase in plasma aminotransferase activity correlated well with the elevation of plasma tumor necrosis factor-α activity. Pretreatment with dexamethasone or 16,16-dimethylprostaglandin E2 attenuated not only the elevation of plasma tumor necrosis factor-α activity but also the increase in plasma aminotransferase activity and improved the survival rate. Passive immunization against tumor necrosis factor-α also showed protective effects. These findings suggest that tumor necrosis factor-α released from activated macrophages may play a crucial role in the pathogenesis of this murine hepatitis.