Role of the Kupffer cell in hepatic carcinogenesis in patients infected with hepatitis C virus

丙型肝炎病毒感染者肝脏枯否细胞数量增加。或者，IL-18是促炎细胞因子，也是通过激活淋巴细胞的抗肿瘤免疫系统的强增强剂。因为，IL-18主要由巨噬细胞产生，并且枯否细胞是肝脏中巨噬细胞的主要细胞群。因此，本研究旨在探讨血清IL-18水平与HCV感染伴或不伴HCC患者枯否细胞数量的关系，包括抗HCV抗体阳性的慢性肝病（CLD）患者（包括慢性肝炎和肝硬化）、HCV相关性HCC患者和HCV阴性的健康受试者。ELISA法检测血清IL-18、IL-12水平。RT-PCR检测肝组织中IL-1和IFN-γ mRNA的表达。在肝脏中使用IL-18和CD68抗巨噬细胞抗体进行免疫组织化学。免疫组化和免疫印迹法检测肝组织中氧化应激标志物8-OHdG、HNE水平，CLD患者血清IL-18和IL-12水平显著高于其他各组。CLD患者Th1细胞因子的mRNA表达增加。免疫组化显示IL-18阳性细胞为枯否细胞。CD68阳性细胞数与血清IL-18水平及肝脏8-OHdG表达呈正相关。肝癌患者经治疗后，高IL-18水平的8-OHdG组患者无病生存率明显低于对照组，提示Kupffer细胞数量和血清IL-18水平的升高可能参与了肝癌的进展。血清IL-18水平对预测肝癌高危人群有一定的实用价值。

The number of Kupffer cells increased in the liver with hepatitis C virus infection. Alternatively, IL-18 is a pro-inflammatory cytokine and also a strong enhancer of anti-tumor immune system by activating lymphocytes. Since, IL-18 is predominantly produced by macrophage and the Kupffer cell is a predominant cell population of macrophages in the liver. Therefore, relationship between serum IL-18 level and population of the Kupffer cell in HCV infected patients with or without HCC was investigated.Chronic liver disease (CLD) patients with anti-HCV antibody including chronic hepatitis and liver cirrhosis, patients bearing HCV related HCC, and healthy HCV negative subjects were included in this study. Serum IL-18, IL-12 levels were measured by ELISA. Messenger RNA expression of IL-1 and interferon (IFN)-γ was measured in the liver tissue by RT-PCR. Immunohistochemistry using IL-18 and CD68 anti-macrophage antibodies were performed in the liver. Moreover, oxidative stress marker 8-OHdG, HNE was assessed by immunohistochemistry and immuno-blotting in the liver.Serum IL-18 and IL-12 level in CLD patients was significantly greater than other groups. Messenger RNA expression of Th1 cytokines was increased in the CLD patients. Immunohistochemistry was revealed that IL-18 positive cell was morphologically identified as the Kupffer cell. The number of CD68 positive cell was positively correlated with serum IL-18 levels and 8-OHdG expressions in the liver. Furthermore, after curative treatment of HCC, the disease free survival was significantly poor in the high IL-18 of 8-OHdG group.In conclusion, increases in the number of the Kupffer cell and serum IL-18 levels could be involved in the progression of HCC. Furthermore, serum IL-18 level is practical to predict the high-risk group of HCC occurrence.