The importance of TNF in the AMD model was explored by preventing its binding to cellular receptors with etanercept. Etanercept pretreatment reduced hepatotoxicity, indicating that TNF has an important role in AMD/LPS-induced liver injury. Because no liver injury was observed after treatment with LPS AMD HEPATOTOXICITY DURING MODEST INFLAMMATION alone, the large TNF peak caused by LPS was not hepatotoxic by itself; however, this amount of TNF could be critical for the induction of hepatocellular injury by potentiating the toxic effect of AMD and/or DEA. Signaling from an activated TNF receptor can lead to lysosomal leakage, mitochondrial damage, and caspase activation (Wullaert et al., 2007) . All three of these events were also found in AMD and DEA cytotoxicity in vitro (Agoston et al., 2003; Spaniol et al., 2001) . Further support for a critical role for TNF came from our in vitro study in Hepa1c1c7 cells in which TNF increased the cytotoxicity of both AMD and DEA. As a proximal proinflammatory cytokine, TNF can also contribute to liver damage by inducing downstream inflammatory events, such as coagulation activation and neutrophil activation (Shaw et al., 2009b; Tukov et al., 2007) . The etanercept treatment herein reduced the ALT activity to half of the level seen in the absence of this inhibitor, whereas the same dose of etanercept reduced the ALT activity almost to control level in trovafloxacin/LPS and sulindac/LPS models (Shaw et al., 2007; Zou et al., 2009a) . This suggests that other factors induced by LPS might act in parallel with TNF in the AMD/LPS model. In other models of potentiation of xenobiotic toxicity by LPS, factors such as neutrophils (Luyendyk et al., 2005) , the coagulation system (Shaw et al., 2009a) , and prostanoids (Ganey et al., 2001) play important roles, and these factors might be relevant in the model presented here.