Tumor necrosis factor-α induces the aberrant expression of mucus core protein-2 in non-neoplastic biliary epithelial cells via the upregulation of CDX2 in chronic cholangitis


Dr Yasuni Nakanuma, Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 920-8640, Japan. Email: pbcpsc@kenroku.kanazawa-u.ac.jp


Aim:  Chronic cholangitis, such as hepatolithiasis, is frequently associated with goblet cell metaplasia and the aberrant expression of mucus core protein-2 (MUC2). In this study, we clarified the role of inflammatory cytokines in the expression of MUC2 in lining biliary epithelial cells (BEC) in chronic cholangitis with an emphasis on CDX2, an intestine-specific transcription factor.

Methods:  We used human hepatolithiatic livers and polycystic kidney (PCK) rats, an animal model of Caroli's disease, and cultured BEC from PCK rats. As a control, extrahepatic biliary obstruction and histologically normal livers and Crj:CD rats were used.

Results:  Immunohistochemically, tumor necrosis factor-α (TNF-α) was expressed in periductal inflammatory cells and BEC of the affected intrahepatic bile ducts with an aberrant expression of MUC2 and CDX2 in hepatolithiasis and the PCK rats. In cultured BEC, TNF-α, interleukin (IL)-1β, IL-6, and interferon-γ induced the expression of CDX2 mRNA, though only TNF-α additionally induced the expression of MUC2 mRNA. The expression of CDX2 mRNA and the MUC2 protein induced in BEC by TNF-α were abolished by pretreatment of nuclear factor-κB inhibitors.

Conclusion:  The aberrant expression of CDX2 and MUC2 in the affected bile ducts showing goblet cell metaplasia was closely associated with TNF-α expressed in periductal infiltrating inflammatory cells and BEC. TNF-α induced the expression of CDX2 and MUC2 in cultured BEC. Taken together, it seems likely that TNF-α plays a role in MUC2 expression via CDX2 upregulation in the bile ducts with chronic cholangitis and goblet cell metaplasia.