TY - JOUR
T1 - MiRNA-506 promotes primary biliary cholangitis-like features in cholangiocytes and immune activation
AU - Erice, Oihane
AU - Munoz-Garrido, Patricia
AU - Vaquero, Javier
AU - Perugorria, Maria J.
AU - Fernandez-Barrena, Maite G.
AU - Saez, Elena
AU - Santos-Laso, Alvaro
AU - Arbelaiz, Ander
AU - Jimenez-Agüero, Raul
AU - Fernandez-Irigoyen, Joaquin
AU - Santamaria, Enrique
AU - Torrano, Verónica
AU - Carracedo, Arkaitz
AU - Ananthanarayanan, Meenakshisundaram
AU - Marzioni, Marco
AU - Prieto, Jesus
AU - Beuers, Ulrich
AU - Oude Elferink, Ronald P.
AU - LaRusso, Nicholas F.
AU - Bujanda, Luis
AU - Marin, Jose J. G.
AU - Banales, Jesus M.
PY - 2018
Y1 - 2018
N2 - Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease associated with autoimmune phenomena targeting intrahepatic bile duct cells (cholangiocytes). Although PBC etiopathogenesis still remains obscure, development of anti-mitochondrial auto-antibodies against pyruvate dehydrogenase complex-E2 (PDC-E2) is a common feature. MicroRNA (miR) dysregulation occurs in liver and immune cells of PBC patients, but their 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 (AE2) and type III inositol 1,4,5-trisphosphate receptor (InsP3R3), leading to cholestasis. Here, the regulation of miR-506 gene expression and its role in cholangiocyte pathophysiology and immune activation was studied. Several pro-inflammatory cytokines overexpressed in PBC livers [such as IL8, IL12, IL17, IL18 and TNFα] 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: i) induced dedifferentiation with downregulation of biliary and epithelial markers together with upregulation of mesenchymal, pro-inflammatory and pro-fibrotic markers; ii) impaired cell proliferation and adhesion; iii) increased oxidative and endoplasmic reticulum (ER) stress; iv) caused DNA damage; and v) 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 ATP production) and PDC-E2 overexpression. Co-culture of miR-506 overexpressing cholangiocytes with PBC immunocytes induced activation and proliferation of PBC immunocytes. different pro-inflammatory 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. This article is protected by copyright. All rights reserved
AB - Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease associated with autoimmune phenomena targeting intrahepatic bile duct cells (cholangiocytes). Although PBC etiopathogenesis still remains obscure, development of anti-mitochondrial auto-antibodies against pyruvate dehydrogenase complex-E2 (PDC-E2) is a common feature. MicroRNA (miR) dysregulation occurs in liver and immune cells of PBC patients, but their 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 (AE2) and type III inositol 1,4,5-trisphosphate receptor (InsP3R3), leading to cholestasis. Here, the regulation of miR-506 gene expression and its role in cholangiocyte pathophysiology and immune activation was studied. Several pro-inflammatory cytokines overexpressed in PBC livers [such as IL8, IL12, IL17, IL18 and TNFα] 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: i) induced dedifferentiation with downregulation of biliary and epithelial markers together with upregulation of mesenchymal, pro-inflammatory and pro-fibrotic markers; ii) impaired cell proliferation and adhesion; iii) increased oxidative and endoplasmic reticulum (ER) stress; iv) caused DNA damage; and v) 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 ATP production) and PDC-E2 overexpression. Co-culture of miR-506 overexpressing cholangiocytes with PBC immunocytes induced activation and proliferation of PBC immunocytes. different pro-inflammatory 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. This article is protected by copyright. All rights reserved
U2 - https://doi.org/10.1002/hep.29533
DO - https://doi.org/10.1002/hep.29533
M3 - Article
C2 - 28922472
SN - 0270-9139
VL - 67
SP - 1420
EP - 1440
JO - Hepatology (Baltimore, Md.)
JF - Hepatology (Baltimore, Md.)
IS - 4
ER -