Role of interleukin-18 and its receptor in hepatocellular carcinoma associated with hepatitis C virus infection

Interleukin (IL)-18 is a proinflammatory cytokine that is up-regulated in patients with hepatitis C virus (HCV) infection, which is the most common underlying disease in hepatocellular carcinoma (HCC). The purpose of our study was to investigate the role of IL-18 in HCC associated with HCV infection. Sixty-five patients with HCC and HCV infections who received curative surgical resections were examined in our study. The expression of the IL-18 receptor was investigated in HCC tissues obtained from these patients and in 2 HCC cell lines. Nuclear factor (NF)-kappaB activity and the expression of Bcl-xL and xIAP mRNA were tested in the cell lines using recombinant human (rh) IL-18. The IL-18 receptor was expressed in both the HCC tissues and the cell lines. NF-kappaB activation and the expression of Bcl-xL and xIAP mRNA were increased by rhIL-18. Moreover, rhIL-18 suppressed the apoptosis of HCC cells which was induced by etoposide in vitro. The overall survival rate (55.4%) was significantly worse in the IL-18 receptor-positive patients than in the IL-18 receptor-negative patients (p = 0.015). In a Cox multivariate analysis, the expression of the IL-18 receptor was found to be a significant predictor of a poor outcome in HCC patients. The expression of the IL-18 receptor and an antiapoptotic mechanism involving NF-kappaB activation in HCC cells may be implicated in a poor patient outcome.