The effect of the free radical scavenger dimethyl sulfoxide (DMSO) on activation of the nuclear transcription factor KB (NF-KB) was investigated in an experimental model of endotoxin-induced liver failure. In galactosamine-sensitized C3Heb/FeJ mice, DMSO (10 mL/kg) effectively inhibited endotoxin-induced hepatic NF-KB activation, suppressed TNF-[alpha] levels in plasma by 86%, attenuated intercellular adhesion molecule-1 (ICAM-1) mRNA formation, blocked hepatic neutrophil accumulation by 79%, and reduced liver injury by 80%. In galactosamine-sensitized mice treated with 20/[mu] g/kg murine TNF-[alpha], DMSO moderately reduced hepatic NF-KB and decreased ICAM-1 mRNA formation and liver injury by 83%, but had no significant effect on hepatic neutrophil accumulation. Thus, DMSO was able to inhibit, at least in part, two critical NF-KB-dependent steps in the pathophysiology, ie, TNF-[alpha] formation and ICAM-1 gene transcription. Our data suggest the involvement of redox-sensitive events in the signal transduction pathway of NF-KB activation in the liver. Inhibition of NF-KB activation correlates with the reduced activation of proinflammatory genes in vivo and the subsequent attenuation of inflammatory liver injury. Thus, antioxidants that are NF-KB inhibitors may have therapeutic potential in endotoxin shock and sepsis.