Distinct Roles of Tumor Necrosis Factor-α and Nitric Oxide in Acute Liver Injury Induced by Carbon Tetrachloride in Mice

Macrophages are known to release a number of different inflammatory mediators with cytotoxic potential. In the present studies we analyzed the role of two macrophage-derived mediators, tumor necrosis factor-α (TNF-α) and nitric oxide, in liver injury induced by carbon tetrachloride (CCl4). Treatment of mice with CCl4 resulted in a dose- and time-dependent induction of centrilobular hepatic necrosis. This was observed within 12 h with 0.3 ml/kg CCl4 and was correlated with increases in serum transaminase levels. CCl4 administration also caused increases in hepatic TNF-α mRNA expression and serum TNF-α levels, as well as inducible nitric oxide synthase (NOS II) protein expression in the liver. To study the role of TNF-α and nitric oxide in hepatotoxicity, we used knockout mice lacking the gene for the 55-kDa TNF-α receptor (TNFR1/p55), the TNF-α cytokine, or NOS II. We found that CCl4 was significantly less effective in inducing hepatotoxicity in mice lacking TNFR1/p55 or the TNF-α cytokine. In contrast, CCl4-induced liver injury was increased in knockout mice lacking the gene for NOS II. This was associated with an increase in hepatic TNF-α mRNA expression and serum TNF-α levels. These data suggest that the hepatoprotective effects of nitric oxide in this model may be due in part to inhibition of TNF-α.