Human biliary epithelial cells secrete and respond to cytokines and hepatocyte growth factors in vitro: Interleukin-6, hepatocyte growth factor and epidermal growth factor promote DNA synthesis in vitro

Authors

  • Koshi Matsumoto,

    1. Pittsburgh Transplant Institute, Department of Pathology, Division of Transplantation, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
    Search for more papers by this author
  • Hiroaki Fujii,

    1. Pittsburgh Transplant Institute, Department of Pathology, Division of Transplantation, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
    Search for more papers by this author
  • George Michalopoulos,

    1. Pittsburgh Transplant Institute, Department of Pathology, Division of Transplantation, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
    Search for more papers by this author
  • John J. Fung,

    1. Pittsburgh Transplant Institute, Department of Pathology, Division of Transplantation, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
    Search for more papers by this author
  • Anthony J. Demetris M.D.

    Corresponding author
    1. Pittsburgh Transplant Institute, Department of Pathology, Division of Transplantation, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
    • E1548 Biomedical Science Tower, University of Pittsburgh, Pittsburgh, PA 15213
    Search for more papers by this author

Abstract

Recombinant growth factors and proinflammatory cytokines were added to primary cultures of human intrahepatic biliary duct epithelia to test for their ability to stimulate DNA synthesis and elicit cytokine production. Interleukin-6 and hepatocyte and epidermal growth factors were found to increase the DNA labeling index of biliary duct epithelium from fourfold to sixfold 24 hr after their addition to primary biliary duct epithelium cultures maintained in serum-free medium. The proliferative responses to all three biliary duct epithelium mitogens peaked within 24 hr, and hepatocyte growth factor was effective over a concentration range of 1.0 to 50 ng/ml, whereas interleukin-6 was effective from 1 to 1,000 U/ml. Insulin-like growth factor, phorbol myristate acetate, interleukin-1β and platelet-derived growth factor BB showed mild stimulatory effects, whereas interleukin-4, γ-interferon, phytohemagglutinin and platelet-derived growth factors AA and AB did not increase DNA synthesis in biliary duct epithelium. Interleukin-1β and phorbol myristate acetate were also shown to induce in a dose-dependent fashion a threefold to fivefold increase of interleukin-6 production as measured by enzyme-linked immunosorbent assay in human primary biliary duct epithelium cultures, when compared with hepatocyte growth factor, epidermal growth factor, insulin-like growth factor, phytohemagglutinin, tumor necrosis factor-α or platelet-derived growth factor. These results show that interleukin-6 participates in growth regulation of human biliary duct epithelium. This could be exerted in a paracrine or autocrine manner. The ability of an inflammatory cytokine to directly promote biliary duct epithelium DNA synthesis provides a link between liver inflammation (or the immune system) and the repair response (growth and development), both of which are important in the histopathology of liver disease. (Hepatology 1994;20:376–382.)

Ancillary