Interferon (IFN)-γ-inducing factor was previously termed interleukin (IL)—18. Although IL-12 is also an IFN-γ—inducing factor, the activity of IL-18 (but not IL-12) in models of sepsis and death is dependent on the intracellular cysteine protease IL-1β converting enzyme (caspase-1). Caspase-1 is required for cleavage of the inactive precursor form of IL-18 into an active cytokine, and caspase-1—deficient mice are resistant to lethal endotoxemia. The absence of IFN-γ (but not IL-1β) in caspase-1—deficient mice is responsible for this resistance. However, the role of IFN-γ in murine defense against gram-negative infection is inconsistent. Mice deficient in IFN-γ are not resistant to lethal endotoxemia but are resistant when treated with neutralizing antibodies to IL-18 and challenged with a lethal injection of some endotoxins. Anti-IL-18 treatment also reduces neutrophil accumulation in liver and lungs. Neutralizing IL-18 with the IL-18 binding protein protects mice against endotoxin- and ischemia-induced hepatic damage. Thus, blockade of IL-18 appears to be a viable clinical target to combat the pathologic consequences of sepsis via IFN-γ mechanisms.