Requirement for interleukin-12 in the pathogenesis of warm hepatic ischemia/reperfusion injury in mice

Hepatic ischemia and reperfusion causes neutrophil-dependent Liver injury. Although the mechanisms of ischemia/reperfusion-induced liver neutrophil re cruitment are somewhat understood, less is known regarding the early events that initiate the inflammatory injury. Using a murine model of partial hep atic ischemia and reperfusion, we evaluated the role of endogenous interleu kin (IL)-12 in this inflammatory response. Hepatic ischemia for 90 minutes and reperfusion for up to 4 hours resulted in hepatocyte expression of IL-1 2. By 8 hours of reperfusion there were large increases in serum levels of interferon-gamma (IFN gamma) and tumor necrosis factor-alpha (TNF alpha). I n addition, hepatic ischemia/reperfusion caused significant increases in li ver neutrophil recruitment, hepatocellular injury, and liver edema, as defi ned by Liver myeloperoxidase content, serum alanine aminotransferase, and l iver wet to dry weight ratios, respectively. In mice treated with neutraliz ing antibody to IL-12 and in mice deficient in the IL-12 p40 gene, ischemia /reperfusion-induced increases in IFN gamma and TNF alpha were greatly dimi nished. These conditions also caused significant reductions in liver myelop eroxidase content and attenuated the parameters of Liver injury. The data s uggest that IL-12 is required for the full induction of injury after hepati c ischemia and reperfusion.