TY - JOUR
T1 - MicroRNA-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.
N1 - Funding Information:
Supported by the Spanish Ministries of Economy and Competitiveness (FIS PI12/00380, FIS PI15/01132, and Miguel Servet Program CON14/ 00129, to J.M.B.; FIS PI14/00399, to M.J.P.; FIS PI16/00598 and SAF2013-40620-R, to J.J.G.M.) cofinanced by Fondo Europeo de Desarrollo Regional (FEDER); Instituto de Salud Carlos III (CIBERehd; EHD15PI05, to J.M.B., L.B., and J.J.G.M.), Junta de Castilla y Leon (SA015U13 and BIO/SA52/15, to J.J.G.M.); Diputación Foral Gipuzkoa (DFG14/007, to L.B.; DFG15/010 and DFG16/004, to J.M.B.); Departments of Industry, Tourism, Trade and Health of the Basque Country (2013111173, to L.B.); Basque Foundation for Innovation and Health Research: EiTB Maratoia (BIO15/CA/016/BD, to J.M.B.); the National Institutes of Health (1R56 DK099470-01, to M.A.). J.M.B. and O.E. were funded by the Asociación Española Contra el Cancer (AECC) and A.S.-L., by the Basque government. M.J. Perugorria is supported by a Ramón Y Cajal award. V.T. is supported by the Fundación Vasca de Innovación e Investigación Sanitarias (BIO15/CA/052), the Department of Health of the Basque Government, and AECC-Bizkaia. A. Carracedo is supported by a Ramón y Cajal award, the Basque Department of Industry, Tourism and Trade (Etortek), ISCIII (PI10/01484, PI13/00031), a FERO VIII Fellowship, the BBVA Foundation, MINECO (SAF2016-79381-R; AEI/FEDER, EU), and a European Research Council Starting Grant (336343). CIBERONC was cofunded with FEDER funds. The Proteomics Unit of Navarrabiomed is a member of Proteored, PRB2-ISCIII, and is supported by grant PT13/0001 of the PE I1D1I 2013-2016 funded by ISCIII and FEDER.
Publisher Copyright:
© 2017 by the American Association for the Study of Liver Diseases.
PY - 2018/4
Y1 - 2018/4
N2 - 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).
AB - 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).
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U2 - 10.1002/hep.29533
DO - 10.1002/hep.29533
M3 - Article
C2 - 28922472
AN - SCOPUS:85042215407
SN - 0270-9139
VL - 67
SP - 1420
EP - 1440
JO - Hepatology
JF - Hepatology
IS - 4
ER -