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Peptide antibiotic human beta‐defensin‐1 and −2 contribute to antimicrobial defense of the intrahepatic biliary tree

Human beta‐defensins (hBDs) are important antimicrobial peptides that contribute to innate immunity at mucosal surfaces. This study was undertaken to investigate the expression of hBD‐1 and hBD‐2 in intrahepatic biliary epithelial cells in specimens of human liver, and 4 cultured cell lines (2 consisting of biliary epithelial cells and 2 cholangiocarcinoma cells). In addition, hBD‐1 and hBD‐2 were assayed in specimens of bile. hBD‐1 was nonspecifically expressed immunohistochemically in intrahepatic biliary epithelium and hepatocytes in all patients studied, but expression of hBD‐2 was restricted to large intrahepatic bile ducts in 8 of 10 patients with extrahepatic biliary obstruction (EBO), 7 of 11 with hepatolithiasis, 1 of 6 with primary biliary cirrhosis (PBC), 1 of 5 with primary sclerosing cholangitis (PSC), 0 of 6 with chronic hepatitis C (CH‐C), and 0 of 11 with normal hepatic histology. hBD‐2 expression was evident in bile ducts exhibiting active inflammation. Serum C reactive protein levels correlated with biliary epithelial expression of hBD‐2. Real‐time PCR revealed that in all of 28 specimens of fresh liver, including specimens from patients with hepatolithiasis, PBC, PSC, CH‐C and normal hepatic histology, hBD‐1 messenger RNA was consistently expressed, whereas hBD‐2 messenger RNA was selectively expressed in biliary epithelium of patients with hepatolithiasis. Immunobloting analysis revealed hBD‐2 protein in bile in 1 of 3 patients with PSC, 1 of 3 with PBC, and each of 6 with hepatolithiasis; in contrast, hBD‐1 was detectable in all bile samples examined. Four cultured biliary epithelial cell lines consistently expressed hBD‐1; in contrast these cell lines did not express hBD‐2 spontaneously but were induced to express hBD‐2 by treatment with Eschericia coli, lipopolysaccharide, interleukin‐1β or tumor necrosis factor‐α. In conclusion, these findings suggest that in the intrahepatic biliary tree, hBD‐2 is expressed in response to local infection and/or active inflammation, whereas hBD‐1 may constitute a preexisting component of the biliary antimicrobial defense system. Supplementary material for this article can be found on the Hepatology website (http:/interscience.wley.com/jpages/0270–9139/suppmat/index.html). (Hepatology 2004;40:925‐932).