Downregulation of the proteasome subunits, transporter, and antigen presentation in hepatocellular carcinoma, and their restoration by interferon-γ
Article first published online: 7 AUG 2002
Journal of Gastroenterology and Hepatology
Volume 17, Issue 8, pages 897–907, August 2002
How to Cite
Matsui, M., Machida, S., Itani-Yohda, T. and Akatsuka, T. (2002), Downregulation of the proteasome subunits, transporter, and antigen presentation in hepatocellular carcinoma, and their restoration by interferon-γ. Journal of Gastroenterology and Hepatology, 17: 897–907. doi: 10.1046/j.1440-1746.2002.02837.x
- Issue published online: 7 AUG 2002
- Article first published online: 7 AUG 2002
- antigen presentation;
- cytotoxic T-lymphocytes;
- histocompatibility leukocyte antigens class I molecules;
AbstractBackground : In our previous study, expressions of human histocompatibility leukocyte antigens class I molecules (HLA-I) and the transporter associated with antigen processing (TAP) 1/2 genes were investigated in seven hepatocellular carcinoma (HCC) cell lines. Two cell lines, Hep-3B and HuH-7, showed a reduced level of TAP, which might cause the low surface expression of HLA-I. In order to understand the downregulation mechanism of antigen presentation in tumors, the two cell lines were further investigated.
Methods : Expressions of HLA-I and antigen presentation-related genes were analyzed by flow cytometry and polymerase chain reaction, respectively. Antigen presentation was tested in 51Cr-release assays.
Results : Flow cytometric analyses revealed low surface expression of HLA-I on Hep-3B and HuH-7 cells. Introduction of HLA-A2 gene did not result in a high surface expression of HLA-A2. This suggested the downregulation of HLA-I expression might be related to defects in the antigen presentation machinery. We then examined expression levels of various antigen presentation-related genes. Hep-3B and HuH-7 demonstrated low expression of the low-molecular-weight protein (LMP) 2, LMP7, TAP1, and HLA-I heavy-chain transcripts. The downregulation of these genes was dissolved by treatment with γ-interferon. Furthermore, allo-specific cytotoxic T lymphocyte (CTL) lines failed to recognize Hep-3B and HuH-7 cells, while they killed IFN-γ-treated Hep-3B and HuH-7 cells.
Conclusions : Our results suggest that defects in the antigen presentation-related molecules might cause downregulation of HLA-I expression, antigen presentation, and subsequently, escape from specific CTL killing. The downregulation could be restored by IFN-γ treatment, suggesting the potential use of IFN-γ for therapeutic purposes.