Biliary innate immunity and cholangiopathy

The intrahepatic biliary tree is a conduit of bile which contains pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) originated from intestinal flora. Human biliary epithelial cells (BEC) express toll-like receptors (TLR) and intracellular adaptor molecules and secrete antibiotic peptides and (pro)inflammatory cytokines via the activation of nuclear transcription factors. However, although human bile contains several PAMPs in normal as well as diseased livers, PAMPs physiologically do not elicit an inflammatory response in the biliary tree, suggesting that tolerance against commensal PAMPs including LPS (endotoxin tolerance) is important in maintaining the homeostasis of biliary innate immunity. Negative regulators of intracellular TLR signalings, peroxisome proliferator activating receptor-gamma (PPAR-gamma) and IRAK-M, are associated with the endotoxin tolerance in BEC. In vivo, PPAR-gamma and IRAK-M are ubiquitously expressed in intrahepatic biliary epithelium, while the expression of PPAR-gamma is reduced in damaged bile ducts of primary biliary cirrhosis (PBC). In addition to antibiotic peptides, several cytokines andchemokines are also secreted from BEC as an innate immune response and these humoral components participate in attracting immunocytes and modulating peribiliary cytokine milieu. BEC have receptors for several cytokines and the expression of TLR in BEC is affected by cytokines, suggesting that biliary innate immunity is regulated by an acquired immunity. A T-helper (Th)1-type cytokine, interferon-gamma, downregulates PPAR-gamma and upregulates TLR, and consequently increases the susceptibility of biliary innate immunity. Because periductal cytokine milieu in PBC is Th1-dominant, the increased susceptibility to PAMPs may be associated with the development of cholangiopathy in PBC. Biliary innate immunity is speculated to be associated with the pathogenesis of biliary diseases as well as the defense against biliary microbial infection.