Increased expression of interleukin-6 and tumor necrosis factor-alpha in pathologic biliary epithelial cells: in situ and culture study

Abstract

We examined the pathologic significance of the expression of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), both proinflammatory cytokines, on intrahepatic biliary epithelial cells, using immunohistochemical and in situ hybridization techniques as well as culture study. IL-6 and TNF-alpha were expressed in the cytoplasm of biliary epithelial cells of damaged small bile ducts and bile ductules, particularly in primary biliary cirrhosis. Their expression on the bile ducts was mild to moderate in other hepatobiliary diseases and mild or absent in normal livers. Signals of IL-6 mRNA and TNF-alpha mRNA were detected in the cytoplasm of biliary epithelial cells, especially in primary biliary cirrhosis. Immunoelectron microscopic study supported this. TNF receptor and to a lesser degree IL-6 receptor alpha-chain were detected on these damaged bile ducts, suggesting an autocrine effect. By Western blotting and enzyme-linked immunosorbent assay, IL-6 and TNF-alpha were frequently detected in gallbladder bile from primary biliary cirrhosis, and their titers were higher compared with other hepatobiliary diseases. Culture of intrahepatic biliary epithelial cells revealed that they expressed IL-6 and secreted IL-6 in the culture media. These results suggest that the intrahepatic biliary epithelial cells are able to synthesize IL-6 and probably TNF-alpha and are involved in the production of bile duct lesions by means of receptor-mediated processes, particularly biliary epithelial proliferation and destruction and autoimmune augmentation, in primary biliary cirrhosis.