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Biliary Innate Immunity: Function and Modulation

DOI: 10.1155/2010/373878

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Biliary innate immunity is involved in the pathogenesis of cholangiopathies in patients with primary biliary cirrhosis (PBC) and biliary atresia. Biliary epithelial cells possess an innate immune system consisting of the Toll-like receptor (TLR) family and recognize pathogen-associated molecular patterns (PAMPs). Tolerance to bacterial PAMPs such as lipopolysaccharides is also important to maintain homeostasis in the biliary tree, but tolerance to double-stranded RNA (dsRNA) is not found. In PBC, CD4-positive Th17 cells characterized by the secretion of IL-17 are implicated in the chronic inflammation of bile ducts and the presence of Th17 cells around bile ducts is causally associated with the biliary innate immune responses to PAMPs. Moreover, a negative regulator of intracellular TLR signaling, peroxisome proliferator-activated receptor- (PPAR ), is involved in the pathogenesis of cholangitis. Immunosuppression using PPAR ligands may help to attenuate the bile duct damage in PBC patients. In biliary atresia characterized by a progressive, inflammatory, and sclerosing cholangiopathy, dsRNA viruses are speculated to be an etiological agent and to directly induce enhanced biliary apoptosis via the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Moreover, the epithelial-mesenchymal transition (EMT) of biliary epithelial cells is also evoked by the biliary innate immune response to dsRNA. 1. Introduction Clarification of the molecular mechanisms of innate immunity and significance of innate immune responses to the pathogenesis of immune-mediated diseases as well as to the defense against infections has progressed steadily since the cloning of Tolls in drosophila and Toll-like receptors (TLRs) in mammals including humans [1, 2]. Innate immunity was initially thought to be limited to immunocompetent cells such as dendritic cells and macrophages, but epithelial cells also possess TLRs and proper innate immune systems. Liver and extrahepatic bile ducts consisting of hepatocytes and biliary epithelial cells (BECs) are also exposed to microorganisms and their components originating from the intestines via portal blood and duodenum. In the gastrointestinal tract, TLRs expressed in intestinal epithelial cells may be involved in innate immunity to maintain mucosal homeostasis and also the development of enterocolitis by producing inflammatory molecules [3]. Similar processes using TLRs may operate in the biliary tree. Human bile is sterile under normal conditions, but bacterial components such as lipopolysaccharide (LPS),

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