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 sever al liver diseases, including allograft rejection wherein intrahepatic bile ducts are infiltrated and damaged by T cells and neutrophils. Loc ally secreted chemotactic cytokines (chemokines) are important signals for leukocyte recruitment to an inflammatory site and include interle ukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-I), potent chemo tactic agents for neutrophils and monocyte or T cells, respectively. I n this study, we demonstrate that primary cultures of human biliary ep ithelial cells (BECs) express and secrete IL-8 and MCP-1, both of whic h are upregulated rapidly and markedly in response to the proinflammat ory cytokines IL-1 and tumor necrosis factor-alpha. Interferon-gamma h ad a differential effect by reducing IL-8 secretion but stimulating MC P-1 secretion. BECs cocultured in transwell chambers below confluent m onolayers 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 t hat human BECs produce and secrete potent, functional chemokines when stimulated by proinflammatory cytokines. The ability of BECs to secret e chemokines and thus to promote leukocyte infiltration into portal tr acts seems likely to be an important cause of bile duct damage in such conditions as liver allograft rejection and may explain the involveme nt of intrahepatic bile ducts in a number of inflammatory liver diseas es.