title: Enhancement of Programmed Death Ligand 2 on Hepatitis C Virus Infected Hepatocytes by Calcineurin Inhibitors.
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.
authors: 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.
authors: Kazuko
authors: K
authors: Koike
authors: Akinobu
authors: A
authors: Takaki
authors: Takahito
authors: T
authors: Yagi
authors: Yoshiaki
authors: Y
authors: Iwasaki
authors: Tetsuya
authors: T
authors: Yasunaka
authors: Hiroshi
authors: H
authors: Sadamori
authors: Susumu
authors: S
authors: Shinoura
authors: Yuzo
authors: Y
authors: Umeda
authors: Ryuichi
authors: R
authors: Yoshida
authors: Daisuke
authors: D
authors: Sato
authors: Daisuke
authors: D
authors: Nobuoka
authors: Masashi
authors: M
authors: Utsumi
authors: Yasuhiro
authors: Y
authors: Miyake
authors: Fusao
authors: F
authors: Ikeda
authors: Hidenori
authors: H
authors: Shiraha
authors: Toshiyoshi
authors: T
authors: Fujiwara
authors: Kazuhide
authors: K
authors: Yamamoto
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D065095:Calcineurin Inhibitors / Q000009:adverse effects*; D045744:Cell Line, Tumor; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000276:immunology / Q000472:pathogenicity; D019694:Hepatitis B, Chronic / Q000276:immunology / Q000378:metabolism / Q000821:virology; D019698:Hepatitis C, Chronic / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D022781:Hepatocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000378:metabolism*; D012008:Recurrence; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation; D014775:Virus Activation / Q000187:drug effects*
chemical_list: D065095:Calcineurin Inhibitors; C573420:ICAM1 protein, human; D007166:Immunosuppressive Agents; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D018799:Intercellular Adhesion Molecule-1