Elevation of serum interleukin-18 levels and activation of Kupffer cells in biliary atresia

Background/Purpose: Interleukin-18 (IL-18)/interferon-γ-inducing factor (IGIF) is a novel proinflammatory cytokine that can induce interferon gamma (IFN-γ). In addition, IL-18 enhances intracellular adhesion molecule- 1 (ICAM-1) expression as well as Fas ligand (FasL) expression, and induces apoptosis in hepatic injury. The aim of this study was to clarify the potential role of IL-18 in the pathogenesis of the progressive inflammation and fibrosis in biliary atresia (BA). Methods: Six children with BA before hepatic portoenterostomy (HPE), 13 with BA including 7 without jaundice and 6 with persistent jaundice after HPE, and 16 healthy controls were examined. Blood samples were obtained preoperatively from 6 patients, after HPE from 13, and after liver transplantation from 4. The IL-18 level was determined by an enzyme-linked immunosorbent assay (ELISA). Immunohistochemically, liver specimens from BA patients were studied using a monoclonal antibody to macrophage-associated antigen (CD68). Results: IL-18 levels were elevated in the patients before HPE compared with those of the controls (349 ± 54 pg/mL v 138 ± 13 pg/mL, P < .0001). After HPE, extremely high concentrations of IL-18 were observed in patients with persistent jaundice (532 ± 95 pg/mL, P < .0001), and the IL-18 levels were significantly high even in the patients without jaundice (249 ± 29 pg/mL, P < 0.005). The high IL-18 level lasted for a long time even in the patients without jaundice after HPE. In contrast, the IL-18 levels immediately decreased after liver transplantation. Immunohistochemically, the number of CD68-positive Kupffer cells was significantly higher, and the size was larger in the livers of the patients than in the controls. The proliferation of CD68-positive cells was much more conspicuous in the liver specimens obtained during liver transplantation than in those at the time of HPE. Conclusions: Our findings showed elevation of serum IL-18 levels and activation of Kupffer cells in BA. IL-18 released from activated Kupffer cells might play an important role in the pathophysiology of the progressive inflammation and fibrosis in BA. Furthermore, IL-18 level may be related to the prognosis in patients with BA. Copyright (C) 2000 by W.B. Saunders Company.