Dataset Information

The Cholangiocyte Adenosine-IL-6 Axis Regulates Survival During Biliary Cirrhosis.

ABSTRACT: Epithelial response to injury is critical to the pathogenesis of biliary cirrhosis, and IL-6 has been suggested as a mediator of this phenomenon. Several liver cell types can secrete IL-6 following activation by various signaling molecules including circulating adenosine. The aims of this study were to assess whether adenosine can induce IL-6 secretion by cholangiocytes via the A2b adenosine receptor (A2bAR) and to determine the effect of A2bAR-sensitive IL-6 release on injury response in biliary cirrhosis. Human normal cholangiocyte H69 cells were used for in vitro studies to determine the mechanism by which adenosine and the A2bAR induce release of IL-6. In vivo, control and A2bAR-deficient mice were used to determine the roles of A2bAR-sensitive IL-6 release in biliary cirrhosis induced by common bile duct ligation (BDL). Additionally, the response to exogenous IL-6 was assessed in C57BL/6 and A2bAR-deficient mice. Adenosine induced IL-6 mRNA expression and protein secretion via A2bAR activation. Although activation of A2bAR induced cAMP and intracellular Ca2+ signals, only the Ca2+ signals were linked to IL-6 upregulation. After BDL, A2bAR-deficient mice have impaired survival, which is further impaired by exogenous IL-6; however, decreased survival is not due to changes in fibrosis and no changes in inflammatory cells. Exogenous IL-6 is associated with the increased presence of bile infarcts. Extracellular adenosine induces cholangiocyte IL-6 release via the A2bAR. This signaling pathway is important in the pathogenesis of injury response in biliary cirrhosis but does not alter fibrosis. Adenosine upregulates IL-6 release by cholangiocytes via the A2bAR in a calcium-sensitive fashion. Mice deficient in A2bAR experience impaired survival after biliary cirrhosis induced by common bile duct ligation independent of changes in fibrosis.

SUBMITTER: Lavoie EG

PROVIDER: S-EPMC5885153 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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The Cholangiocyte Adenosine-IL-6 Axis Regulates Survival During Biliary Cirrhosis.

Lavoie Elise G EG Fausther Michel M Goree Jessica R JR Dranoff Jonathan A JA

Gene expression 20170911 4

Epithelial response to injury is critical to the pathogenesis of biliary cirrhosis, and IL-6 has been suggested as a mediator of this phenomenon. Several liver cell types can secrete IL-6 following activation by various signaling molecules including circulating adenosine. The aims of this study were to assess whether adenosine can induce IL-6 secretion by cholangiocytes via the A2b adenosine receptor (A2bAR) and to determine the effect of A2bAR-sensitive IL-6 release on injury response in biliar ...[more]

PMID: 28893353

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Project description:Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease with a slowly progressive course. Without treatment, most patients eventually develop fibrosis and cirrhosis of the liver and may need liver transplantation in the late stage of disease. PBC primarily affects women (female preponderance 9-10:1) with a prevalence of up to 1 in 1,000 women over 40 years of age. Common symptoms of the disease are fatigue and pruritus, but most patients are asymptomatic at first presentation. The diagnosis is based on sustained elevation of serum markers of cholestasis, i.e., alkaline phosphatase and gamma-glutamyl transferase, and the presence of serum antimitochondrial antibodies directed against the E2 subunit of the pyruvate dehydrogenase complex. Histologically, PBC is characterized by florid bile duct lesions with damage to biliary epithelial cells, an often dense portal inflammatory infiltrate and progressive loss of small intrahepatic bile ducts. Although the insight into pathogenetic aspects of PBC has grown enormously during the recent decade and numerous genetic, environmental, and infectious factors have been disclosed which may contribute to the development of PBC, the precise pathogenesis remains enigmatic. Ursodeoxycholic acid (UDCA) is currently the only FDA-approved medical treatment for PBC. When administered at adequate doses of 13-15 mg/kg/day, up to two out of three patients with PBC may have a normal life expectancy without additional therapeutic measures. The mode of action of UDCA is still under discussion, but stimulation of impaired hepatocellular and cholangiocellular secretion, detoxification of bile, and antiapoptotic effects may represent key mechanisms. One out of three patients does not adequately respond to UDCA therapy and may need additional medical therapy and/or liver transplantation. This review summarizes current knowledge on the clinical, diagnostic, pathogenetic, and therapeutic aspects of PBC.

Project description:Biliary atresia (BA) is a fibroinflammatory obstruction of the extrahepatic biliary tree in neonates. While intrahepatic bile duct proliferation is universal at diagnosis, bile duct paucity develops later. We hypothesized that polarized T helper lymphocyte responses orchestrate progression of intrahepatic biliary injury in this disease. Interleukin 17A (IL-17A)-green fluorescent protein, cluster of differentiation 11c (CD11c)/diphtheria toxin receptor, and IL-17 receptor A-/- mice were used to examine T-lymphocyte polarization, inflammatory leukocyte recruitment, and biliary injury in rhesus rotavirus-induced BA. Multiparameter flow cytometry and automated image analysis of immunostaining were applied to liver tissue samples from infants with BA. In the mouse model, activated CD4+ lymphocytes started to emerge in the liver on day 8 after viral challenge, while innate immune responses were waning. Plasma IL-17A levels rose concomitantly with hepatic accumulation of T helper 17 lymphocytes and myeloid dendritic cells. Targeted depletion of CD11c+ dendritic cells diminished hepatic IL-17A production and ameliorated intrahepatic bile duct injury. Recombinant IL-17A induced expression of chemokine (C-C motif) ligand 2 in neonatal cholangiocytes in vitro, and blockade of the corresponding chemokine (C-C motif) receptor 2 reduced recruitment of inflammatory macrophages to the liver in vivo. Genetic disruption of IL-17A signaling was associated with down-regulation of hepatic Ccl2/Ccr2 messenger RNA expression, reduced infiltration of the liver with inflammatory Ly6Chi macrophages, and improved survival. In the liver of infants with BA, cholangiocytes were found to express IL-17 receptor A, and the prevalence of IL-17A+ cells was positively correlated with the degree of CD68+ macrophage infiltration at diagnosis. Hepatic CD4+ lymphocytes were chief producers of IL-17A in patients with progressive disease undergoing liver transplantation.These findings identify the dendritic cell-T helper 17-macrophage axis as a target for the development of strategies to block progression of intrahepatic bile duct injury in patients with BA. (Hepatology 2017;65:174-188).

Dataset Information

The Cholangiocyte Adenosine-IL-6 Axis Regulates Survival During Biliary Cirrhosis.

Publications

The Cholangiocyte Adenosine-IL-6 Axis Regulates Survival During Biliary Cirrhosis.

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