Role of interleukin-18 in intrahepatic inflammatory cell recruitment in acute liver injury

Although the innate immune system has been demonstrated to play important roles as the first line of defense against various infections, little is known about the interactions between intrahepatic inflammatory cells and the cytokine network in the liver. Here, we examined the role of IL-18 in IHL recruitment in acute liver injury. C57BL/6 mice were injected with an alpha CD40 mAb, and their serum IL-18 levels were observed to increase, with subsequent recruitment of IHLs into the liver. NKT cells were involved in this liver injury, as the serum ALT levels were reduced in NKT KO mice through the suppression of macrophage and monocyte migration and cytokine production. In contrast, depletion of neutrophils exacerbated the liver injury associated with high levels of TNF-alpha and IL-18 and increased numbers of macrophages and monocytes. Treatment with a neutralizing antibody against IL-18 reduced the serum ALT levels and inflammatory cell accumulation in the liver. Finally, additional administration of rIL-18 with alpha CD40 injection caused severe liver injury with increased IFN-gamma production by NK cells. In conclusion, these findings demonstrate that IL-18 modulates liver inflammation by the recruitment of inflammatory cells, including NKT cells, macrophages, monocytes, and neutrophils. J. Leukoc. Biol. 89: 433-442; 2011.