Biliary Innate Immunity: Function and Modulation

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-γ (PPARγ), is involved in the pathogenesis of cholangitis. Immunosuppression using PPARγ 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]  I. Mackay,et al.  CX3CL1 (fractalkine): A signpost for biliary inflammation in primary biliary cirrhosis , 2010, Hepatology.

[2]  K. Isse,et al.  Periductal interleukin‐17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in primary biliary cirrhosis , 2009, Clinical and experimental immunology.

[3]  K. Isse,et al.  Epithelial–mesenchymal transition induced by biliary innate immunity contributes to the sclerosing cholangiopathy of biliary atresia , 2009, The Journal of pathology.

[4]  J. Kuebler,et al.  Incidence of hepatotropic viruses in biliary atresia , 2009, European Journal of Pediatrics.

[5]  K. Isse,et al.  Induction of innate immune response and absence of subsequent tolerance to dsRNA in biliary epithelial cells relate to the pathogenesis of biliary atresia , 2008, Liver international : official journal of the International Association for the Study of the Liver.

[6]  M. Pekalski,et al.  Epithelial–mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease , 2008, Laboratory Investigation.

[7]  Yasunori Sato,et al.  Cholangiocytes with mesenchymal features contribute to progressive hepatic fibrosis of the polycystic kidney rat. , 2007, The American journal of pathology.

[8]  Yosuke Osawa,et al.  TLR4 enhances TGF-β signaling and hepatic fibrosis , 2007, Nature Medicine.

[9]  K. Isse,et al.  Innate immune response to double‐stranded RNA in biliary epithelial cells is associated with the pathogenesis of biliary atresia , 2007, Hepatology.

[10]  F. Sallusto,et al.  Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17–producing human T helper cells , 2007, Nature Immunology.

[11]  K. Isse,et al.  IL‐8 expression by biliary epithelial cells is associated with neutrophilic infiltration and reactive bile ductules , 2007, Liver international : official journal of the International Association for the Study of the Liver.

[12]  K. Isse,et al.  Endotoxin tolerance in human intrahepatic biliary epithelial cells is induced by upregulation of IRAK‐M , 2006, Liver international : official journal of the International Association for the Study of the Liver.

[13]  P. Flemming,et al.  Expression of the interferon-induced Mx proteins in biliary atresia. , 2006, Journal of pediatric surgery.

[14]  K. Isse,et al.  Interferon γ accelerates NF-κB activation of biliary epithelial cells induced by Toll-like receptor and ligand interaction , 2006, Journal of Clinical Pathology.

[15]  T. Uchiyama,et al.  Lipoteichoic acid may affect the pathogenesis of bile duct damage in primary biliary cirrhosis , 2006, Autoimmunity.

[16]  Jiri Zavadil,et al.  TGF-β and epithelial-to-mesenchymal transitions , 2005, Oncogene.

[17]  Masahiro Ito,et al.  Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis , 2005, Laboratory Investigation.

[18]  K. Isse,et al.  Th1 cytokine–induced downregulation of PPARγ in human biliary cells relates to cholangitis in primary biliary cirrhosis , 2005, Hepatology.

[19]  K. Isse,et al.  Fractalkine and CX3CR1 are involved in the recruitment of intraepithelial lymphocytes of intrahepatic bile ducts , 2005, Hepatology.

[20]  T. Mcclanahan,et al.  IL-23 drives a pathogenic T cell population that induces autoimmune inflammation , 2005, The Journal of experimental medicine.

[21]  S. Akira,et al.  Toll-like receptors in innate immunity. , 2004, International immunology.

[22]  T. Hirayama,et al.  Peptide antibiotic human beta‐defensin‐1 and ‐2 contribute to antimicrobial defense of the intrahepatic biliary tree , 2004, Hepatology.

[23]  J. Peters,et al.  Peroxisome proliferator‐activated receptor α protects against alcohol‐induced liver damage , 2004 .

[24]  J. Peters,et al.  Peroxisome proliferator-activated receptor alpha protects against alcohol-induced liver damage. , 2004, Hepatology.

[25]  Shizuo Akira,et al.  Toll-like receptor signalling , 2004, Nature Reviews Immunology.

[26]  D. Podolsky,et al.  Mechanisms of cross hyporesponsiveness to Toll-like receptor bacterial ligands in intestinal epithelial cells. , 2004, Gastroenterology.

[27]  Jean Paul Thiery,et al.  Epithelial-mesenchymal transitions in development and pathologies. , 2003, Current opinion in cell biology.

[28]  K. Isse,et al.  Lipopolysaccharide Activates Nuclear Factor-KappaB through Toll-Like Receptors and Related Molecules in Cultured Biliary Epithelial Cells , 2003, Laboratory Investigation.

[29]  A. Ljungh,et al.  Increased prevalence of seropositivity for non-gastric Helicobacter species in patients with autoimmune liver disease. , 2003, Journal of medical microbiology.

[30]  K. Shiraki,et al.  15-Deoxy-Δ-12-14-PGJ2 Regulates Apoptosis Induction and Nuclear Factor-κB Activation Via a Peroxisome Proliferator-Activated Receptor-γ–Independent Mechanism in Hepatocellular Carcinoma , 2003, Laboratory Investigation.

[31]  J. Neuberger,et al.  Does a betaretrovirus infection trigger primary biliary cirrhosis? , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[32]  H. Shirasawa,et al.  Lack of evidence for reovirus infection in tissues from patients with biliary atresia and congenital dilatation of the bile duct. , 2003, Journal of hepatology.

[33]  M. Benito,et al.  The epithelial mesenchymal transition confers resistance to the apoptotic effects of transforming growth factor Beta in fetal rat hepatocytes. , 2002, Molecular cancer research : MCR.

[34]  P. Szavay,et al.  The role of reovirus type 3 infection in an established murine model for biliary atresia. , 2002, European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery ... [et al] = Zeitschrift fur Kinderchirurgie.

[35]  Charles A. Janeway,et al.  IRAK-M Is a Negative Regulator of Toll-like Receptor Signaling , 2002, Cell.

[36]  M. Kaplan,et al.  Identification of HLA-A2–restricted CD8+ Cytotoxic T Cell Responses in Primary Biliary Cirrhosis , 2002, The Journal of Experimental Medicine.

[37]  K. Tsuneyama,et al.  Scavenger cells with gram-positive bacterial lipoteichoic acid infiltrate around the damaged interlobular bile ducts of primary biliary cirrhosis. , 2001, Journal of hepatology.

[38]  Mourad Sahbatou,et al.  Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease , 2001, Nature.

[39]  S. Dooley,et al.  Expression of Smads during in vitro transdifferentiation of hepatic stellate cells to myofibroblasts. , 2001, Biochemical and biophysical research communications.

[40]  K. Tsuneyama,et al.  Molecular identification of bacterial 16S ribosomal RNA gene in liver tissue of primary biliary cirrhosis: Is Propionibacterium acnes involved in granuloma formation? , 2001, Hepatology.

[41]  K. Tsuneyama,et al.  Frequent molecular identification of Campylobacter but not Helicobacter genus in bile and biliary epithelium in hepatolithiasis , 2001, The Journal of pathology.

[42]  Y. Terauchi,et al.  Endogenous PPARγ mediates anti-inflammatory activity in murine ischemia-reperfusion injury , 2001 .

[43]  E. Gold,et al.  Risk factors for primary biliary cirrhosis in a cohort of patients from the United States , 2001, Hepatology.

[44]  S. Sheen-Chen,et al.  Bacteriology and antimicrobial choice in hepatolithiasis. , 2000, American journal of infection control.

[45]  K. Tsuneyama,et al.  Amplification and sequence analysis of partial bacterial 16S ribosomal RNA gene in gallbladder bile from patients with primary biliary cirrhosis. , 2000, Journal of hepatology.

[46]  J. Taneera,et al.  Identification of Helicobacter pylori and OtherHelicobacter Species by PCR, Hybridization, and Partial DNA Sequencing in Human Liver Samples from Patients with Primary Sclerosing Cholangitis or Primary Biliary Cirrhosis , 2000, Journal of Clinical Microbiology.

[47]  K. Tanikawa,et al.  Abnormal accumulation of endotoxin in biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis. , 1998, Journal of hepatology.

[48]  V. Bafna,et al.  Human beta-defensin 2 is a salt-sensitive peptide antibiotic expressed in human lung. , 1998, The Journal of clinical investigation.

[49]  K. Tyler,et al.  Detection of reovirus RNA in hepatobiliary tissues from patients with extrahepatic biliary atresia and choledochal cysts , 1998, Hepatology.

[50]  Z. Shen,et al.  Hepatic Helicobacter species identified in bile and gallbladder tissue from Chileans with chronic cholecystitis. , 1998, Gastroenterology.

[51]  P. Colombani,et al.  Lack of Evidence for Rotavirus by Polymerase Chain Reaction/Enzyme Immunoassay of Hepatobiliary Samples from Children with Biliary Atresia , 1997, Pediatric Research.

[52]  K. Schäkel,et al.  Detection of group C rotavirus in infants with extrahepatic biliary atresia. , 1996, The Journal of infectious diseases.

[53]  N. Mcintyre,et al.  Natural history of bacteriuria in women with primary biliary cirrhosis and the effect of antimicrobial therapy in symptomatic and asymptomatic groups. , 1995, Gut.

[54]  H. Ishibashi,et al.  Hla Drb4 0101-restricted Immunodominant T Cell Autoepitope of Pyruvate Dehydrogenase Complex in Primary Biliary Cirrhosis: Evidence of Molecular Mimicry in Human Autoimmune Diseases , 1995 .

[55]  P. Ogra,et al.  Group A Rotaviruses Produce Extrahepatic Biliary Obstruction in Orally Inoculated Newborn Mice , 1993, Pediatric Research.

[56]  Y. Nakanuma,et al.  Expression of vimentin in proliferating and damaged bile ductules and interlobular bile ducts in nonneoplastic hepatobiliary diseases. , 1992, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[57]  J. Costerton,et al.  Defense system in the biliary tract against bacterial infection , 1992, Digestive Diseases and Sciences.

[58]  K. Saito,et al.  Lactoferrin and lysozyme in the intrahepatic bile duct of normal livers and hepatolithiasis. An immunohistochemical study. , 1992, Journal of hepatology.

[59]  Y. Nakanuma,et al.  Secretory component and immunoglobulins in the intrahepatic biliary tree and peribiliary gland in normal livers and hepatolithiasis , 1989, Gastroenterologia Japonica.

[60]  R. Hall,et al.  Lack of correlation between infection with reovirus 3 and extrahepatic biliary atresia or neonatal hepatitis. , 1988, The Journal of pediatrics.

[61]  I. Mackay,et al.  Identification and specificity of a cDNA encoding the 70 kd mitochondrial antigen recognized in primary biliary cirrhosis. , 1987, Journal of immunology.

[62]  Y. Kress,et al.  Detection of Reovirus Type 3 in the Porta Hepatis of an Infant with Extrahepatic Biliary Atresia: Ultrastructural and Immunocytochemical Study , 1984, Hepatology.

[63]  S. Sherlock,et al.  Bacteriuria and primary biliary cirrhosis. , 1984, Gut.

[64]  M. Horwitz,et al.  Biliary atresia and reovirus type 3 infection. , 1982, The New England journal of medicine.

[65]  W. Marsden.  I and J , 2012 .

[66]  Ji Won Kim,et al.  Evidence for the epithelial to mesenchymal transition in biliary atresia fibrosis. , 2008, Human pathology.

[67]  K. Isse,et al.  Interferon gamma accelerates NF-kappaB activation of biliary epithelial cells induced by Toll-like receptor and ligand interaction. , 2006, Journal of clinical pathology.

[68]  K. Shiraki,et al.  15-deoxy-delta-12-14-PGJ2 regulates apoptosis induction and nuclear factor-kappaB activation via a peroxisome proliferator-activated receptor-gamma-independent mechanism in hepatocellular carcinoma. , 2003, Laboratory investigation; a journal of technical methods and pathology.

[69]  M. Kaplan,et al.  Identification of HLA-A2-restricted CD8(+) cytotoxic T cell responses in primary biliary cirrhosis: T cell activation is augmented by immune complexes cross-presented by dendritic cells. , 2002, The Journal of experimental medicine.

[70]  Y. Terauchi,et al.  Endogenous PPAR gamma mediates anti-inflammatory activity in murine ischemia-reperfusion injury. , 2001, Gastroenterology.

[71]  M. Osnes,et al.  Lipopolysaccharides and beta-glucuronidase activity in choledochal bile in relation to choledocholithiasis. , 1997, Digestion.

[72]  H. Baum,et al.  M2 mitochondrial antibodies and urinary rough mutant bacteria in patients with primary biliary cirrhosis and in patients with recurrent bacteriuria. , 1993, Journal of hepatology.

[73]  J. Lefkowitch.  Bile ductular cholestasis: an ominous histopathologic sign related to sepsis and "cholangitis lenta". , 1982, Human pathology.