Hepatocellular carcinoma (HCC) is one of the most common malignancies in areas with endemic hepatitis virus infections, 1,2 which strongly suggests that hepatitis virus-related damage to the hepatocytes could contribute to HCC development. We demonstrated that the activity of hepatitis in chronic liver disease closely correlated with the intrahepatic recurrence after the operation of HCC. 3 Although the immunological mechanism in chronic hepatitis virus infection has not been clearly defined, it has been assumed that T-cellmediated cytotoxicity is responsible for the hepatocyte injury. In fact, the messenger RNA of the inflammatory cytokines, such as interferon gamma (IFN-␥) and interleukin-2, was preferentially detected in patients with increased hepatitis activity using reverse-transcriptase polymerase chain reaction (RT-PCR) in liver tissue. 4 Because HCC develops in chronic liver disease in which the host immune responses take place to excess, the escape from T-cell-mediated cytotoxicity is thought to be an essential role in the development and outgrowth of HCC.IFN-␥ is produced by activated T lymphocytes and naturalkiller cells, and plays an important role in the host defense mechanism by exerting antiviral, antiproliferative, immunoregulatory, and proinflammatory activities. 5-7 IFN-␥ exerts its pleiotrophic biological effects by transcriptional regulation of the expression of numerous genes, such as major histocompatibility complex (MHC) class I, FcrRI, and Fas through interaction with a specific cell membrane receptor (IFN-␥ receptor [IFN-␥-R]). 6,[8][9][10][11][12][13][14] Although the hepatocytes in the normal liver express weak or no IFN-␥-R, those in acute and chronic liver diseases up-regulated the expression of IFN-␥-R, and this up-regulation might play a partial role in the immunoregulatory action of IFN-␥ during liver inflammation. 15 Kaplan et al. demonstrated that IFN-␥-R ␣-chain knock-out mice developed tumors more rapidly and frequently than did the wild-type controls when bred onto a background deficient in the p53 tumor-suppressor gene, as well as when treated with the chemical carcinogen, 3-methylcolanthrene. 16 They proposed the concept that the actions of IFN-␥ on the tumor cells serve an extrinsic tumor-suppressor mechanism in immunocompetent hosts. Accordingly, blocking the signal transduction of IFN-␥ in HCC might contribute to escape from host immune surveillance in chronic liver disease in which many infiltrating lymphocytes produce IFN-␥. However, it is unclear how HCC blocks the signal transduction of IFN-␥. We examined the degree of tumor infiltration of IFN-␥-positive lymphocytes and the expression of IFN-␥-R, and IFN-␥-inducible genes, such as MHC class I and Fas, in HCC and investigated whether the modulation of IFN-␥-R expression was one of the mechanisms blocking the signal transducAbbreviations: HCC, hepatocellular carcinoma; IFN-␥, interferon gamma; RT-PCR, reverse-transcriptase polymerase chain reaction; MHC, major histocompatibility complex; IFN-␥-R, IFN-␥ receptor; AFP,...
