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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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Effect of the peroxisome proliferator-activated receptor γ (PPARγ) ligand, 15d-PGJ2, on lipopolysaccharide (LPS, TLR4 ligand)- and peptidoglycan (PGN, TLR2 ligand)-induced NF-κB activation in cultured human biliary epithelial cells (BECs). BECs are pretreated in the presence or absence of 15d-PGJ2 (20 μM) before stimulation with LPS or peptidoglycan. Pretreatment with 15d-PGJ2 significantly prevents PAMP-induced NF-κB activation (* < .05).
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fig6: Effect of the peroxisome proliferator-activated receptor γ (PPARγ) ligand, 15d-PGJ2, on lipopolysaccharide (LPS, TLR4 ligand)- and peptidoglycan (PGN, TLR2 ligand)-induced NF-κB activation in cultured human biliary epithelial cells (BECs). BECs are pretreated in the presence or absence of 15d-PGJ2 (20 μM) before stimulation with LPS or peptidoglycan. Pretreatment with 15d-PGJ2 significantly prevents PAMP-induced NF-κB activation (* < .05).

Mentions: Several PPARγ ligands have been identified, including the prostaglandin D metabolite 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and thiazolidinedione derivatives. 15d-PGJ2 functions as an endogenous ligand for PPARγ and attenuates the activation of NF-κB by preventing the phosphorylation of its inhibitor protein (I-κB). In cultured human BECs, 15d-PGJ2 treatment attenuates PAMP (LPS or peptidoglycan)-induced NF-κB activation and also TNF-α production (Figure 6). PPARγ ligands provide protection against biliary inflammation in PBC, but 15d-PGJ2 inhibited NF-κB's activation independent of PPARγ [67, 68]. In fact, a PPARγ antagonist (GW9662) partially blocked the inhibitory effects of 15d-PGJ2 on NF-κB activity. Therefore, 15d-PGJ2 is expected to be effective in the antiinflammatory treatment of bile ducts with reduced as well as preserved PPARγ expression in PBC. Because PPARγ is a key immunomodulatory molecule, a reduction in its expression in the bile ducts of PBC liver may be important to the immunopathogenesis of chronic cholangitis. Therefore, immunosuppression using PPARγ ligands may help to reduce bile duct damage in PBC.


Biliary innate immunity: function and modulation.

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

Effect of the peroxisome proliferator-activated receptor γ (PPARγ) ligand, 15d-PGJ2, on lipopolysaccharide (LPS, TLR4 ligand)- and peptidoglycan (PGN, TLR2 ligand)-induced NF-κB activation in cultured human biliary epithelial cells (BECs). BECs are pretreated in the presence or absence of 15d-PGJ2 (20 μM) before stimulation with LPS or peptidoglycan. Pretreatment with 15d-PGJ2 significantly prevents PAMP-induced NF-κB activation (* < .05).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig6: Effect of the peroxisome proliferator-activated receptor γ (PPARγ) ligand, 15d-PGJ2, on lipopolysaccharide (LPS, TLR4 ligand)- and peptidoglycan (PGN, TLR2 ligand)-induced NF-κB activation in cultured human biliary epithelial cells (BECs). BECs are pretreated in the presence or absence of 15d-PGJ2 (20 μM) before stimulation with LPS or peptidoglycan. Pretreatment with 15d-PGJ2 significantly prevents PAMP-induced NF-κB activation (* < .05).
Mentions: Several PPARγ ligands have been identified, including the prostaglandin D metabolite 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and thiazolidinedione derivatives. 15d-PGJ2 functions as an endogenous ligand for PPARγ and attenuates the activation of NF-κB by preventing the phosphorylation of its inhibitor protein (I-κB). In cultured human BECs, 15d-PGJ2 treatment attenuates PAMP (LPS or peptidoglycan)-induced NF-κB activation and also TNF-α production (Figure 6). PPARγ ligands provide protection against biliary inflammation in PBC, but 15d-PGJ2 inhibited NF-κB's activation independent of PPARγ [67, 68]. In fact, a PPARγ antagonist (GW9662) partially blocked the inhibitory effects of 15d-PGJ2 on NF-κB activity. Therefore, 15d-PGJ2 is expected to be effective in the antiinflammatory treatment of bile ducts with reduced as well as preserved PPARγ expression in PBC. Because PPARγ is a key immunomodulatory molecule, a reduction in its expression in the bile ducts of PBC liver may be important to the immunopathogenesis of chronic cholangitis. Therefore, immunosuppression using PPARγ ligands may help to reduce bile duct damage in PBC.

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