Distinct roles of tumor necrosis factor-alpha and nitric oxide in acute liver injury induced by carbon tetrachloride in mice

Macrophages are known to release a number of different inflammatory mediato rs with cytotoxic potential. In the present studies we analyzed the role of two macrophage-derived mediators, tumor necrosis factor-alpha (TNF-alpha) and nitric oxide, in liver injury induced by carbon tetrachloride (CCl4). T reatment 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-alpha mRNA express ion and serum TNF-alpha levels, as well as inducible nitric oxide synthase (NOS II) protein expression in the liver. To study the role of TNF-alpha an d nitric oxide in hepatotoxicity, we used knockout mice lacking the gene fo r the 55-kDa TNF-alpha receptor (TNFR1/p55), the TNF-alpha cytokine, or NOS II. We found that CCl4 was significantly less effective in inducing hepato toxicity in mice lacking TNFR1/p55 or the TNF-alpha cytokine. In contrast, CCl4-induced liver injury was increased in knockout mice lacking the gene f or NOS II. This was associated with an increase in hepatic TNF-alpha mRNA e xpression and serum TNF-alpha levels. These data suggest that the hepatopro tective effects of nitric oxide in this model may be due in part to inhibit ion of TNF-alpha. (C) 2001 Academic Press.