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Biliary innate immunity: function and modulation.

Harada K, Nakanuma Y - Mediators Inflamm. (2010)

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan. kenichih@med.kanazawa-u.ac.jp

ABSTRACT
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-gamma (PPARgamma), is involved in the pathogenesis of cholangitis. Immunosuppression using PPARgamma 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.

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Related in: MedlinePlus

Immunohistochemical staining for human beta defensin (hBD)-1 (a) and hBD-2 (b). (a) Normal liver. Septal bile ducts are positive for hBD-1. (b) Extrahepatic biliary obstruction. Biliary epithelium of the intrahepatic large bile duct showing cholangitis strongly expresses hBD-2.
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fig2: Immunohistochemical staining for human beta defensin (hBD)-1 (a) and hBD-2 (b). (a) Normal liver. Septal bile ducts are positive for hBD-1. (b) Extrahepatic biliary obstruction. Biliary epithelium of the intrahepatic large bile duct showing cholangitis strongly expresses hBD-2.

Mentions: Defensins are antimicrobial peptides identified as key elements in innate immunity. Structurally, they are divided into α- and β-defensins. The β-defensin family is distributed in the epithelium of several organs, constituting an important barrier at mucosal surfaces. So far, human β-defensins (hBD-1 to -6) have been identified.  hBD-1 is constitutively expressed in cultured BECs and diffusely distributed in the cytoplasm of intrahepatic bile ducts irrespective of anatomical levels [42] (Figure 2). Moreover, because hBD-1 is constantly detectable in bile samples, hBD-1 it is believed to play a role in the constitutive antimicrobial defense of the hepatobiliary system [42]. This may be why biliary tract infections are rare and bile is sterile under physiological conditions, though the biliary tree is potentially exposed to enteric bacteria. In contrast, hBD-2 is not detected in BECs cultured without a stimulant, but de novo expression is found in LPS- or E. coli-treated BECs. In vivo, hBD-2 expression is restricted to the intrahepatic large bile ducts and peribiliary glands, in particular, showing cholangitis in extrahepatic biliary obstruction and hepatolithiasis (Figure 2) [42]. Because in these diseased livers, enteric bacteria are mostly cultivable in bile, the participation of bacteria-related cholangitis is closely associated with the hBD-2 expression in BECs. Therefore, hBD-1 plays a constitutive role in biliary antimicrobial defense, while hBD-2 expression is induced in response to local infections and may play a role in additional antimicrobial defenses.


Biliary innate immunity: function and modulation.

Harada K, Nakanuma Y - Mediators Inflamm. (2010)

Immunohistochemical staining for human beta defensin (hBD)-1 (a) and hBD-2 (b). (a) Normal liver. Septal bile ducts are positive for hBD-1. (b) Extrahepatic biliary obstruction. Biliary epithelium of the intrahepatic large bile duct showing cholangitis strongly expresses hBD-2.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2926654&req=5

fig2: Immunohistochemical staining for human beta defensin (hBD)-1 (a) and hBD-2 (b). (a) Normal liver. Septal bile ducts are positive for hBD-1. (b) Extrahepatic biliary obstruction. Biliary epithelium of the intrahepatic large bile duct showing cholangitis strongly expresses hBD-2.
Mentions: Defensins are antimicrobial peptides identified as key elements in innate immunity. Structurally, they are divided into α- and β-defensins. The β-defensin family is distributed in the epithelium of several organs, constituting an important barrier at mucosal surfaces. So far, human β-defensins (hBD-1 to -6) have been identified.  hBD-1 is constitutively expressed in cultured BECs and diffusely distributed in the cytoplasm of intrahepatic bile ducts irrespective of anatomical levels [42] (Figure 2). Moreover, because hBD-1 is constantly detectable in bile samples, hBD-1 it is believed to play a role in the constitutive antimicrobial defense of the hepatobiliary system [42]. This may be why biliary tract infections are rare and bile is sterile under physiological conditions, though the biliary tree is potentially exposed to enteric bacteria. In contrast, hBD-2 is not detected in BECs cultured without a stimulant, but de novo expression is found in LPS- or E. coli-treated BECs. In vivo, hBD-2 expression is restricted to the intrahepatic large bile ducts and peribiliary glands, in particular, showing cholangitis in extrahepatic biliary obstruction and hepatolithiasis (Figure 2) [42]. Because in these diseased livers, enteric bacteria are mostly cultivable in bile, the participation of bacteria-related cholangitis is closely associated with the hBD-2 expression in BECs. Therefore, hBD-1 plays a constitutive role in biliary antimicrobial defense, while hBD-2 expression is induced in response to local infections and may play a role in additional antimicrobial defenses.

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan. kenichih@med.kanazawa-u.ac.jp

ABSTRACT
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-gamma (PPARgamma), is involved in the pathogenesis of cholangitis. Immunosuppression using PPARgamma 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.

Show MeSH
Related in: MedlinePlus