Elevation of serum interleukin-18 levels and activation of Kupffer cells in biliary atresia.
OBJECTIVE
Interleukin-18 (IL-18)/interferon-gamma-inducing factor (IGIF) is a novel proinflammatory cytokine that can induce interferon gamma (IFN-gamma). 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.
Urushihara
N
N
Department of Surgery, Okayama University Medical School, Japan.
Iwagaki
H
H
Yagi
T
T
Kohka
H
H
Kobashi
K
K
Morimoto
Y
Y
Yoshino
T
T
Tanimoto
T
T
Kurimoto
M
M
Tanaka
N
N
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D017209:Apoptosis; D001656:Biliary Atresia / Q000097:blood / Q000209:etiology* / Q000276:immunology / Q000601:surgery; D002648:Child; D002675:Child, Preschool; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007223:Infant; D020382:Interleukin-18 / Q000097:blood*; D007728:Kupffer Cells / Q000276:immunology / Q000502:physiology*; D008099:Liver / Q000276:immunology / Q000473:pathology; D016031:Liver Transplantation; D011171:Portoenterostomy, Hepatic; D011379:Prognosis; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D020382:Interleukin-18; C067980:CD68 antigen, human; D000097382:CD68 Molecule