Hepatic ischemia and reperfusion causes neutrophildependent liver injury. Although the mechanisms of ischemia/reperfusion-induced liver neutrophil recruitment are somewhat understood, less is known regarding the early events that initiate the inflammatory injury. Using a murine model of partial hepatic ischemia and reperfusion, we evaluated the role of endogenous interleukin (IL)-12 in this inflammatory response. Hepatic ischemia for 90 minutes and reperfusion for up to 4 hours resulted in hepatocyte expression of IL-12. By 8 hours of reperfusion there were large increases in serum levels of interferon-␥ (IFN␥) and tumor necrosis factor-␣ (TNF␣). In addition, hepatic ischemia/reperfusion caused significant increases in liver neutrophil recruitment, hepatocellular injury, and liver edema, as defined by liver myeloperoxidase content, serum alanine aminotransferase, and liver wet to dry weight ratios, respectively. In mice treated with neutralizing antibody to IL-12 and in mice deficient in the IL-12 p40 gene, ischemia/ reperfusion-induced increases in IFN␥ and TNF␣ were greatly diminished. These conditions also caused significant reductions in liver myeloperoxidase content and attenuated the parameters of liver injury. The data suggest that IL-12 is required for the full induction of injury after hepatic ischemia and reperfusion. (HEPATOLOGY 1999;30: 1448-1453.)Hepatic ischemia occurring during trauma or hemorrhage, or under controlled situations such as liver resectional surgery or transplantation, may lead to inflammatory liver injury during hepatic reperfusion. 1-3 Local organ injury and dysfunction caused by ischemia/reperfusion is likely a direct result of the released products (oxidants, proteases, lipids, etc.) of activated neutrophils that have accumulated in the liver parenchyma. 4,5 In the initial stages of this injury the proinflammatory cytokines, tumor necrosis factor-␣ (TNF␣) and interleukin (IL)-1, are induced in liver. 6,7 TNF␣ is known to upregulate liver expression of vascular endothelial cell adhesion molecules (i.e., intracellular adhesion molecule-1), and CXC chemokines, such as epithelial neutrophil-activating protein and macrophage inflammatory protein-2. [8][9][10] The combined effects of adhesion molecules and CXC chemokines results in neutrophil adhesion, transmigration and accumulation in liver. Although the downstream mechanisms responsible for neutrophil recruitment and liver injury are somewhat understood, less is known regarding the early events that propagate this inflammatory response.The cornerstone of most inflammatory responses, including hepatic ischemia/reperfusion injury appears to be the production of the proinflammatory cytokines TNF␣ and IL-1. Blockade of either TNF␣ or IL-1 ameliorates inflammatory injury in a number of animal models. However, clinical trials involving humans with sepsis and involving blocking interventions for TNF␣ or IL-1 have been largely unsuccessful, 11,12 suggesting the participation of other mediators in the development of inflammatory tissue injur...