Abstract
Biliary innate immunity is involved in the pathogenesis of cholangiopathies in cases of biliary disease. Cholangiocytes possess Toll-like receptors (TLRs) which recognize pathogen-associated molecular patterns (PAMPs) and play a pivotal role in the innate immune response. 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. Moreover, in primary biliary cirrhosis (PBC) and biliary atresia, biliary innate immunity is closely associated with the dysregulation of the periductal cytokine milieu and the induction of biliary apoptosis and epithelial-mesenchymal transition (EMT), forming in disease-specific cholangiopathy. Biliary innate immunity is associated with the pathogenesis of various cholangiopathies in biliary diseases as well as biliary defense systems.
Highlights
Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and hepatolithiasis in adults and biliary atresia and choledochal cyst in infants are biliary diseases in which different anatomical levels of the biliary tree are affected and characterized by cholangiopathy
A Th1-type cytokine, IFN-γ upregulates the mRNA expression of TLR2-TLR5 and accelerates the upregulation of PAMPinduced nuclear factor-κB (NF-κB) activation in cholangiocytes, suggesting that a Th1-dominant peribiliary milieu leads to the increased susceptibility to pathogen-associated molecular patterns (PAMPs) and the production of inflammatory cytokines and chemokines from biliary epithelial cells (BECs) [20]
IL-1 receptor-associated kinase- (IRAK-)M mRNA expression was upregulated by stimulation with double-stranded RNA (dsRNA) (TLR3 ligand), no tolerance to the dsRNA was found in cultured BECs. This is reasonable because the intracellular signaling of TLR3 is a myeloid differentiation factor 88 (MyD88)-independent pathway, that is, the dsRNA-related response is not affected by IRAK-M [17]
Summary
Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and hepatolithiasis in adults and biliary atresia and choledochal cyst in infants are biliary diseases in which different anatomical levels of the biliary tree are affected and characterized by cholangiopathy. In particular, may be responsible for the chronic proliferative cholangitis associated with hepatolithiasis [1, 6]. These findings indicate that cholangiocytes are exposed to bacterial PAMPs under physiological as well as pathological conditions. This review summarizes our current understanding of the biliary innate immune system against microbial infections including the various mechanisms employed by negative regulators and their associations with the pathogenesis of cholangiopathy in biliary diseases. Biliary atresia Reovirus Rotavirus Cytomegalovirus Adenovirus Enterovirus Ebstein-Barr virus
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