Suda Takahiro, Tatsumi Tomohide, Nishio Akira, Kegasawa Tadashi, Yoshioka Teppei, Yamada Ryoko, Furuta Kunimaro, Kodama Takahiro, Shigekawa Minoru, Hikita Hayato, Sakamori Ryotaro, Fukuhara Takasuke, Matsuura Yoshiharu, Takehara Tetsuo
Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan.
Department of Molecular Virology Research Institute for Microbial Diseases, Osaka University Suita Japan.
Hepatol Commun. 2018 Sep 25;2(10):1247-1258. doi: 10.1002/hep4.1240. eCollection 2018 Oct.
Natural killer cells (NK cells) play an essential role in the immunological mechanism underlying chronic hepatitis C (CHC). Impairment of NK cell function facilitates persistent infection with hepatitis C virus (HCV) and hepatocellular carcinogenesis. However, the mechanism by which NK cell activity is suppressed in CHC is not completely understood. In this study, we focused on carcinoembryonic antigen-related cell-adhesion molecule 1 (CEACAM1). CEACAM1 is thought to suppress NK cell function. We examined the effect of CEACAM1 on NK cell function in CHC. We investigated the function of CEACAM1 using Huh7.5.1 cells and the HCV-Japanese fulminant hepatitis (JFH)-1 strain. We analyzed serum CEACAM1 level, NK cell function, and CEACAM1 messenger RNA (mRNA) level in human liver samples. Levels of CEACAM1 on the cell surface, CEACAM1 mRNA levels, and soluble CEACAM1 levels in supernatants were significantly higher in Huh7.5.1 cells infected with JFH-1 (Huh7.5.1/JFH-1 cells) than in Huh7.5.1 cells. Significantly higher NK cell cytotoxicity was observed toward K562 cells after coculture with CEACAM1 knockout Huh7.5.1/JFH-1 cells than after coculture with Huh7.5.1/JFH-1 cells. CEACAM1 expression was induced by the HCV E2 glycoprotein in HCV infection. Significantly higher serum CEACAM1 levels were detected in patients with CHC compared with healthy subjects and patients who achieved sustained virological responses. The expression of CD107a on NK cells from patients with CHC was negatively correlated with serum CEACAM1 levels. Significantly higher levels of CEACAM1 mRNA were detected in HCV-infected livers compared with uninfected livers. CEACAM1 expression was induced in hepatocytes following HCV infection and decreased NK cell cytotoxicity. These results demonstrate a possible role for CEACAM1 in the pathogenesis of CHC and hepatocellular carcinoma progression.
自然杀伤细胞（NK细胞）在慢性丙型肝炎（CHC）的免疫机制中起着至关重要的作用。NK细胞功能受损会促进丙型肝炎病毒（HCV）的持续感染和肝细胞癌变。然而，CHC中NK细胞活性被抑制的机制尚未完全明确。在本研究中，我们聚焦于癌胚抗原相关细胞黏附分子1（CEACAM1）。CEACAM1被认为可抑制NK细胞功能。我们研究了CEACAM1对CHC中NK细胞功能的影响。我们使用Huh7.5.1细胞和HCV-日本暴发性肝炎（JFH）-1毒株研究CEACAM1的功能。我们分析了人肝样本中的血清CEACAM1水平、NK细胞功能和CEACAM1信使核糖核酸（mRNA）水平。感染JFH-1的Huh7.5.1细胞（Huh7.5.1/JFH-1细胞）的细胞表面CEACAM1水平、CEACAM1 mRNA水平和上清液中可溶性CEACAM1水平显著高于Huh7.5.1细胞。与Huh7.5.1/JFH-1细胞共培养后相比，与CEACAM1基因敲除的Huh7.5.1/JFH-1细胞共培养后，对K562细胞观察到显著更高的NK细胞细胞毒性。在HCV感染中，CEACAM1表达由HCV E2糖蛋白诱导。与健康受试者和实现持续病毒学应答的患者相比，CHC患者血清CEACAM1水平显著更高。CHC患者NK细胞上CD107a的表达与血清CEACAM1水平呈负相关。与未感染肝脏相比，在HCV感染的肝脏中检测到显著更高水平的CEACAM1 mRNA。HCV感染后肝细胞中诱导了CEACAM1表达并降低了NK细胞细胞毒性。这些结果证明了CEACAM1在CHC发病机制和肝细胞癌进展中可能发挥的作用。
