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Abnormal Expression of ERα in Cholangiocytes of Patients With Primary Biliary Cholangitis Mediated Intrahepatic Bile Duct Inflammation.

ABSTRACT: ERα, one of the classical receptors of estrogen, has been found to be abnormally up-regulated in patients with primary biliary cholangitis (PBC), which is an important factor leading to ductopenia. ERα-mediated signaling pathways are involved in proliferation of human intrahepatic biliary epithelial cells (HiBECs) and portal inflammation. Our previous studies have shown that the expression levels of ERα in the liver tissues of PBC patients are positively correlated with the levels of serum pro-inflammatory cytokines. The present study was designed to assess the relationship between abnormal ERα expression in small bile ducts and the progression of PBC. We examined the levels of multiple cytokines and analyzed their relationship with clinical parameters of livers functions in a cohort of 43 PBC patients and 45 healthy controls (HC). The levels of ERα expression and the relation with the levels of cytokines were further assessed. The localization of cytokines and ERα-mediated signaling pathways in liver were examined using immunohistochemistry. The possible underlying mechanisms of these alterations in PBC were explored in vitro. Our results demonstrated that the levels of IL-6, IL-8, and TNF-α were increased in PBC patients, and positively correlated with the serum AKP levels and ERα expression levels. Moreover, the expression of these cytokines were up-regulated in HiBECs that were stimulated with 17β-estradiol and PPT (an ERα agonist) and they also were positive in intrahepatic bile duct of PBC patients. The ERα-mediated expression of pro-inflammatory cytokines was induced by JNK, P38, and STAT3 phosphorylation in HiBECs. In addition, the CD54 expression was increased in HiBECs after ERα activation, which induced peripheral blood monouclear cells (PBMCs) recruitment. In conclusion, the present study highlighted a key role of abnormal ERα expression in inducing an inflammatory phenotype of HiBECs, which was critical in the development of inflammation and damage in small bile duct.

SUBMITTER: Cao H

PROVIDER: S-EPMC6907097 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease associated with autoimmune phenomena targeting intrahepatic bile duct cells (cholangiocytes). Although its etiopathogenesis remains obscure, development of antimitochondrial autoantibodies against pyruvate dehydrogenase complex E2 is a common feature. MicroRNA (miR) dysregulation occurs in liver and immune cells of PBC patients, but its functional relevance is largely unknown. We previously reported that miR-506 is overexpressed in PBC cholangiocytes and directly targets both Cl- / HCO3- anion exchanger 2 and type III inositol 1,4,5-trisphosphate receptor, leading to cholestasis. Here, the regulation of miR-506 gene expression and its role in cholangiocyte pathophysiology and immune activation was studied. Several proinflammatory cytokines overexpressed in PBC livers (such as interleukin-8 [IL8], IL12, IL17, IL18, and tumor necrosis factor alpha) stimulated miR-506 promoter activity in human cholangiocytes, as revealed by luciferase reporter assays. Experimental overexpression of miR-506 in cholangiocytes dysregulated the cell proteomic profile (by mass spectrometry), affecting proteins involved in different biological processes including mitochondrial metabolism. In cholangiocytes, miR-506 (1) induced dedifferentiation with down-regulation of biliary and epithelial markers together with up-regulation of mesenchymal, proinflammatory, and profibrotic markers; (2) impaired cell proliferation and adhesion; (3) increased oxidative and endoplasmic reticulum stress; (4) caused DNA damage; and (5) sensitized to caspase-3-dependent apoptosis induced by cytotoxic bile acids. These events were also associated with impaired energy metabolism in mitochondria (proton leak and less adenosine triphosphate production) and pyruvate dehydrogenase complex E2 overexpression. Coculture of miR-506 overexpressing cholangiocytes with PBC immunocytes induced activation and proliferation of PBC immunocytes. CONCLUSION:Different proinflammatory cytokines enhance the expression of miR-506 in biliary epithelial cells; miR-506 induces PBC-like features in cholangiocytes and promotes immune activation, representing a potential therapeutic target for PBC patients. (Hepatology 2018;67:1420-1440).

Project description:BackgroundRaoultella Planticola is a facultative anaerobic, gram-negative, water- and soil-dwelling rod bacterium rarely reported as a cause of human disease. However, the number of reported R. planticola infections is growing, without a concomitant increase in research on the microbe or its pathogenesis. Previous genomic studies demonstrating genetic similarities between R. planticola and Klebsiella pneumoniae suggest that capsule biosynthesis, mucoid phenotype, biofilm production, and lipopolysaccharide (endotoxin) synthesis may all be potential virulence factors of R. planticola. We present a unique case of R. planticola infection of the biliary tract 5 years after biliary surgery in a patient with no previously documented risk factors. We also use in silico techniques to predict virulence factors of R. planticola.Case presentationThis case report is the first to discuss a R. planticola infection in the biliary tract of late onset post-surgery (5 years) in a Caucasian patient with no previously documented risk factors.ConclusionsAn in-depth search of the current literature did not yield other similar cases of R. planticola infections. Moreover, to the best of our knowledge, our case is the first case of R. planticola isolated from post-endoscopic retrograde cholangiopancreatography (ERCP) as part of biliary sepsis not associated with gastroenteritis. The late onset of the infection in our patient and the results of the in silico analysis suggest that R. planticola may have survived exposure to the host immune system through the creation of an intracellular biofilm or in a non-culturable but viable state (NCBV) for the 5-year period. The in silico analysis also suggests that biofilms, enterobactin, and mucoid phenotype may play a role in the pathogenesis of R. planticola. However, further research is needed to illuminate the significance of pili, capsule biosynthesis, and lipopolysaccharide (LPS) in the virulence of R. planticola. Lastly, as our patient did not have any risk factors previously associated with R. planticola, we suggest that biliary tract stricture, cholecystitis, and prior surgery may be possible novel risk factors.

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Abnormal Expression of ERα in Cholangiocytes of Patients With Primary Biliary Cholangitis Mediated Intrahepatic Bile Duct Inflammation.

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