Antiproliferative effects of interferon alpha on hepatic progenitor cells in vitro and in vivo

Authors

  • Rebecca Lim,

    1. School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia
    2. School of Biochemical and Chemical Sciences, University of Western Australia, Nedlands, Western Australia
    Search for more papers by this author
  • Belinda Knight,

    1. School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia
    2. Western Australian Institute of Medical Research, Perth, Western Australia
    Search for more papers by this author
  • Keyur Patel,

    1. Duke Clinical Research Institute and Division of Gastroenterology, Duke University, Durham, North Carolina
    Search for more papers by this author
  • John G. McHutchison,

    1. Duke Clinical Research Institute and Division of Gastroenterology, Duke University, Durham, North Carolina
    Search for more papers by this author
  • George C. Yeoh,

    1. School of Biochemical and Chemical Sciences, University of Western Australia, Nedlands, Western Australia
    2. Western Australian Institute of Medical Research, Perth, Western Australia
    Search for more papers by this author
  • John K. Olynyk

    Corresponding author
    1. School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia
    2. Western Australian Institute of Medical Research, Perth, Western Australia
    3. Department of Gastroenterology, Fremantle Hospital, Fremantle, Western Australia
    • School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital Campus, PO Box 480, Fremantle 6959, Western Australia
    Search for more papers by this author
    • fax: 618-9431-2977


  • Potential conflict of interest: Dr. McHutchison is on the speakers' bureau for and received research grants from Roche and Schering-Plough. He is a consultant and scientific advisor for Schering-Plough. This study was partially funded by a grant from Schering-Plough.

Abstract

Hepatic progenitor cells (called oval cells in rodents) proliferate during chronic liver injury. They have been suggested as targets of malignant transformation in chronic liver diseases, including chronic hepatitis C. Interferon alpha therapy reduces the risk of hepatocellular carcinoma (HCC) in chronic hepatitis C regardless of viral clearance. The aim of this study was to determine whether interferon alpha could reduce the risk of HCC by modifying preneoplastic events in the hepatic progenitor cell population. Pre- and post-treatment liver biopsies were evaluated for changes in the hepatic progenitor cell population in 16 patients with non-responding chronic hepatitis C. Interferon alpha–based treatment significantly reduced the numbers of c-kit–positive hepatic progenitor cells by 50%. To determine the mechanism of cell number reduction, the effects of interferon alpha on murine hepatic progenitor cells were studied in vitro. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) proliferation assay and proliferating cell nuclear antigen staining showed that interferon alpha had a dose-dependent, anti-proliferative effect. Interferon alpha stimulated hepatocytic and biliary differentiation of the oval cell lines reflected by increased expression of albumin and cytokeratin19 accompanied by decreased expression of alphafetoprotein and Thy-1. To validate these results in vivo, mice were placed on the choline-deficient, ethionine-supplemented diet to induce liver injury and oval cell proliferation and treated with pegylated interferon alpha 2b for 2 weeks. This resulted in a significant four-fold reduction in the number of oval cells (P < .05). In conclusion, interferon alpha–based treatment reduced the number of hepatic progenitor cells in chronic liver injury by modulating apoptosis, proliferation, and differentiation. (HEPATOLOGY 2006;43:1074–1083.)

Ancillary