Promotion of leukocyte transendothelial cell migration by chemokines derived from human biliary epithelial cells in vitro.

Biliary epithelial cells are the focus of inflammatory damage in several liver diseases, including allograft rejection wherein intrahepatic bile ducts are infiltrated and damaged by T cells and neutrophils. Locally secreted chemotactic cytokines (chemokines) are important signals for leukocyte recruitment to an inflammatory site and include interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1), potent chemotactic agents for neutrophils and monocyte or T cells, respectively. In this study, we demonstrate that primary cultures of human biliary epithelial cells (BECs) express and secrete IL-8 and MCP-1, both of which are upregulated rapidly and markedly in response to the proinflammatory cytokines IL-1 and tumor necrosis factor-alpha. Interferon-gamma had a differential effect by reducing IL-8 secretion but stimulating MCP-1 secretion. BECs cocultured in transwell chambers below confluent monolayers of endothelial cells promoted the transendothelial migration of neutrophils, which was blocked by antibodies to CD18 or CD11b but only partially inhibited by blocking antibodies to IL-8. We conclude that human BECs produce and secrete potent, functional chemokines when stimulated by proinflammatory cytokines. The ability of BECs to secrete chemokines and thus to promote leukocyte infiltration into portal tracts seems likely to be an important cause of bile duct damage in such conditions as liver allograft rejection and may explain the involvement of intrahepatic bile ducts in a number of inflammatory liver diseases.