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Enhancement of Programmed Death Ligand 2 on Hepatitis C Virus Infected Hepatocytes by Calcineurin Inhibitors.

Koike K, Takaki A, Yagi T, Iwasaki Y, Yasunaka T, Sadamori H, Shinoura S, Umeda Y, Yoshida R, Sato D, Nobuoka D, Utsumi M, Miyake Y, Ikeda F, Shiraha H, Fujiwara T, Yamamoto K - Transplantation (2015)

Bottom Line: Treatment of hepatoma cell lines with CNIs resulted in increased PD-L2 expression, especially in combination with HCV core or NS3 protein.The PD-L2 is highly expressed on CH-C-OLT hepatocytes, whereas HCV proteins, in combination with CNIs, induce high expression of PD-L2 resulting in elevated expression of ICAM-1.These findings demonstrate the effect of CNIs on inducing PD-L2 and subsequent ICAM-1 expression, effects that may produce inflammatory cell infiltration in post-OLT hepatitis C.

View Article: PubMed Central - PubMed

Affiliation: 1 Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Japan. 2 Department of Gastroenterological Surgery Transplant and Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Japan. 3 Health Service Center, Okayama University, Okayama, Japan.

ABSTRACT

Background: Post orthotopic liver transplantation (OLT) viral hepatitis is an immunological condition where immune cells induce hepatitis during conditions of immune-suppression. The immune-regulatory programmed death-1 (PD-1)/PD-ligand 1 system is acknowledged to play important roles in immune-mediated diseases. However, the PD-1/PD-L2 interaction is not well characterized, with PD-L2 also exhibiting an immunostimulatory function. We hypothesized that this atypical molecule could affect the recurrence of post-OLT hepatitis. To test this hypothesis, we conducted immunohistochemical staining analysis and in vitro analysis of PD-L2.

Methods: The expression of PD-L2 was evaluated in liver biopsy specimens from patients with chronic hepatitis B (n = 15), post-OLT hepatitis B (n = 8), chronic hepatitis C (n = 48), and post-OLT hepatitis C (CH-C-OLT) (n = 14). The effect of calcineurin inhibitors (CNIs) and hepatitis C virus (HCV) on PD-L2 expression was investigated in hepatoma cell lines.

Results: The PD-L2 was highly expressed on CH-C-OLT hepatocytes. Treatment of hepatoma cell lines with CNIs resulted in increased PD-L2 expression, especially in combination with HCV core or NS3 protein. Transfection of cell lines with PD-L2 containing plasmid resulted in high intercellular adhesion molecule-1 (ICAM-1) expression, which might enhance hepatitis activity.

Conclusions: The PD-L2 is highly expressed on CH-C-OLT hepatocytes, whereas HCV proteins, in combination with CNIs, induce high expression of PD-L2 resulting in elevated expression of ICAM-1. These findings demonstrate the effect of CNIs on inducing PD-L2 and subsequent ICAM-1 expression, effects that may produce inflammatory cell infiltration in post-OLT hepatitis C.

No MeSH data available.


Related in: MedlinePlus

Immunohistochemical staining of programmed death ligand 2 (PD-L2) in liver. The negative staining pattern is shown on the left center of the figure. A, Left: representative sinusoidal staining pattern of PD-L2. The expression of PD-L2 was evaluated according to the staining intensity and scored as follows: 0, negative; 1, weak expression; 2, moderate expression; 3, strong expression. Right: sinusoidal staining in different disease states. B, Left: representative hepatocyte staining pattern of PD-L2. Scoring of staining intensity is the same as in sinusoidal tissue (0, 1, 2, 3). Right: hepatocyte staining in different disease states.
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Figure 1: Immunohistochemical staining of programmed death ligand 2 (PD-L2) in liver. The negative staining pattern is shown on the left center of the figure. A, Left: representative sinusoidal staining pattern of PD-L2. The expression of PD-L2 was evaluated according to the staining intensity and scored as follows: 0, negative; 1, weak expression; 2, moderate expression; 3, strong expression. Right: sinusoidal staining in different disease states. B, Left: representative hepatocyte staining pattern of PD-L2. Scoring of staining intensity is the same as in sinusoidal tissue (0, 1, 2, 3). Right: hepatocyte staining in different disease states.

Mentions: Immunohistochemical analysis revealed PD-L2 staining in sinusoidal cells and/or hepatocytes. Among the 84 tissue samples evaluated, sinusoidal PD-L2 expression levels were scored as 0, 1, 2, and 3 in 11 (13.0%), 35 (41.6%), 31 (36.9%), and 7 (8.3%) cases, respectively (Figure 1A). PD-L2 expression levels in hepatocytes were scored as 0, 1, 2, and 3 in 47 (55.9%), 25 (29.7%), 9 (10.7%), and 3 (3.5%) cases, respectively (Figure 1B). Sinusoidal PD-L2 staining scores were higher than in hepatocytes and showed no significant differences among the disease groups. However, PD-L2 staining in hepatocytes of the CH-C-OLT group was significantly higher than that in the other groups. Additionally, PD-L2 staining in CH-B-OLT hepatocytes was remarkably low.


Enhancement of Programmed Death Ligand 2 on Hepatitis C Virus Infected Hepatocytes by Calcineurin Inhibitors.

Koike K, Takaki A, Yagi T, Iwasaki Y, Yasunaka T, Sadamori H, Shinoura S, Umeda Y, Yoshida R, Sato D, Nobuoka D, Utsumi M, Miyake Y, Ikeda F, Shiraha H, Fujiwara T, Yamamoto K - Transplantation (2015)

Immunohistochemical staining of programmed death ligand 2 (PD-L2) in liver. The negative staining pattern is shown on the left center of the figure. A, Left: representative sinusoidal staining pattern of PD-L2. The expression of PD-L2 was evaluated according to the staining intensity and scored as follows: 0, negative; 1, weak expression; 2, moderate expression; 3, strong expression. Right: sinusoidal staining in different disease states. B, Left: representative hepatocyte staining pattern of PD-L2. Scoring of staining intensity is the same as in sinusoidal tissue (0, 1, 2, 3). Right: hepatocyte staining in different disease states.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4539199&req=5

Figure 1: Immunohistochemical staining of programmed death ligand 2 (PD-L2) in liver. The negative staining pattern is shown on the left center of the figure. A, Left: representative sinusoidal staining pattern of PD-L2. The expression of PD-L2 was evaluated according to the staining intensity and scored as follows: 0, negative; 1, weak expression; 2, moderate expression; 3, strong expression. Right: sinusoidal staining in different disease states. B, Left: representative hepatocyte staining pattern of PD-L2. Scoring of staining intensity is the same as in sinusoidal tissue (0, 1, 2, 3). Right: hepatocyte staining in different disease states.
Mentions: Immunohistochemical analysis revealed PD-L2 staining in sinusoidal cells and/or hepatocytes. Among the 84 tissue samples evaluated, sinusoidal PD-L2 expression levels were scored as 0, 1, 2, and 3 in 11 (13.0%), 35 (41.6%), 31 (36.9%), and 7 (8.3%) cases, respectively (Figure 1A). PD-L2 expression levels in hepatocytes were scored as 0, 1, 2, and 3 in 47 (55.9%), 25 (29.7%), 9 (10.7%), and 3 (3.5%) cases, respectively (Figure 1B). Sinusoidal PD-L2 staining scores were higher than in hepatocytes and showed no significant differences among the disease groups. However, PD-L2 staining in hepatocytes of the CH-C-OLT group was significantly higher than that in the other groups. Additionally, PD-L2 staining in CH-B-OLT hepatocytes was remarkably low.

Bottom Line: Treatment of hepatoma cell lines with CNIs resulted in increased PD-L2 expression, especially in combination with HCV core or NS3 protein.The PD-L2 is highly expressed on CH-C-OLT hepatocytes, whereas HCV proteins, in combination with CNIs, induce high expression of PD-L2 resulting in elevated expression of ICAM-1.These findings demonstrate the effect of CNIs on inducing PD-L2 and subsequent ICAM-1 expression, effects that may produce inflammatory cell infiltration in post-OLT hepatitis C.

View Article: PubMed Central - PubMed

Affiliation: 1 Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Japan. 2 Department of Gastroenterological Surgery Transplant and Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Japan. 3 Health Service Center, Okayama University, Okayama, Japan.

ABSTRACT

Background: Post orthotopic liver transplantation (OLT) viral hepatitis is an immunological condition where immune cells induce hepatitis during conditions of immune-suppression. The immune-regulatory programmed death-1 (PD-1)/PD-ligand 1 system is acknowledged to play important roles in immune-mediated diseases. However, the PD-1/PD-L2 interaction is not well characterized, with PD-L2 also exhibiting an immunostimulatory function. We hypothesized that this atypical molecule could affect the recurrence of post-OLT hepatitis. To test this hypothesis, we conducted immunohistochemical staining analysis and in vitro analysis of PD-L2.

Methods: The expression of PD-L2 was evaluated in liver biopsy specimens from patients with chronic hepatitis B (n = 15), post-OLT hepatitis B (n = 8), chronic hepatitis C (n = 48), and post-OLT hepatitis C (CH-C-OLT) (n = 14). The effect of calcineurin inhibitors (CNIs) and hepatitis C virus (HCV) on PD-L2 expression was investigated in hepatoma cell lines.

Results: The PD-L2 was highly expressed on CH-C-OLT hepatocytes. Treatment of hepatoma cell lines with CNIs resulted in increased PD-L2 expression, especially in combination with HCV core or NS3 protein. Transfection of cell lines with PD-L2 containing plasmid resulted in high intercellular adhesion molecule-1 (ICAM-1) expression, which might enhance hepatitis activity.

Conclusions: The PD-L2 is highly expressed on CH-C-OLT hepatocytes, whereas HCV proteins, in combination with CNIs, induce high expression of PD-L2 resulting in elevated expression of ICAM-1. These findings demonstrate the effect of CNIs on inducing PD-L2 and subsequent ICAM-1 expression, effects that may produce inflammatory cell infiltration in post-OLT hepatitis C.

No MeSH data available.


Related in: MedlinePlus