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

库普弗细胞在丙型肝炎病毒感染者肝癌发生中的作用

• 批准号: 13671293
• 负责人: KONO Hiroshi
• 金额: $ 2.3万
• 依托单位: University of Yamanashi, Faculty of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671293/
• 关键词: Hepatocellular Carcinoma; Oxidative stress; Kupffer cell; Interleukin-18; Tumor immune system in the liver; Chronic Hepatitis C

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.

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CD 68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Th 1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。CD 68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。

项目成果

Akira Maki, Hiroshi Kono, et al.: "Decreased CD3 ζ molecules of T lymphocytes from patients with hepatocellular carcinoma associated with hepatitis C virus"Hepatology Research. (In press). (2003)

Akira Maki、Hiroshi Kono 等人：“与丙型肝炎病毒相关的肝细胞癌患者的 T 淋巴细胞 CD3 分子减少”《肝病学研究》（2003 年出版）。

Asakawa, M., and Kono, H., et al.: "Significance of serum interleukin-18 level as predictor of hepatocellular carcinoma in patients with hepatitis C virus"Hepatology Research. (in press). (2003)

Asakawa, M. 和 Kono, H. 等人：“血清白细胞介素 18 水平作为丙型肝炎病毒患者肝细胞癌预测因子的意义”肝病学研究。