Decreased Expression of Vitamin D Receptor Affects an Immune Response in Primary Biliary Cholangitis via the VDR-miRNA155-SOCS1 Pathway.
Primary biliary cholangitis (PBC) is an immune-mediated cholestatic disease. Vitamin D receptor (VDR)-dependent signaling constrains an inflammatory response by targeting the miRNA155-SOCS1 (suppressor of cytokine signaling 1) axis. The VDR-miRNA155-SOCS1 pathway was investigated in the context of the autoimmune response associated with PBC. Human liver tissues from non-cirrhotic PBC (n= 22), cirrhotic PBC (n= 22), cirrhotic primary sclerosing cholangitis (PSC,n=13), controls (n= 23), and peripheral blood mononuclear cells (PBMC) obtained from PBC (n= 16) and PSC (n= 10) patients and healthy subjects (n= 11) were used for molecular analyses. VDR mRNA and protein expressions were substantially reduced in PBC livers (51% and 59%, respectively). Correspondingly, the decrease of SOCS1 protein expression in PBC livers, after normalization to a marker of lymphocytes and forkhead family transcriptional regulator box P3 (FOXP3, marker of Treg), was observed, and this phenomenon was accompanied by enhanced miRNA155 expression. In PSC livers, protein expressions of VDR and SOCS1 were comparable to the controls. However, in PBM cells, protein expressions of VDR and SOCS1 were considerably decreased in both PBC and PSC. We demonstrated that VDR/miRNA155-modulated SOCS1 expression is decreased in PBC which may lead to insufficient negative regulation of cytokine signaling. These findings suggest that the decreased VDR signaling in PBC could be of importance in the pathogenesis of PBC.
Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland. agnieszkakempinska@interia.eu.
Agnieszka
A
Kempinska-Podhorodecka
Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland. milkiewm@pum.edu.pl.
Malgorzata
M
Milkiewicz
Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland. wasikula@gmail.com.
Urszula
U
Wasik
Department of General Transplant and Liver Surgery, Medical University of Warsaw, 02-097 Warszawa, Poland. jligocka@gmail.com.
Joanna
J
Ligocka
Department of General Transplant and Liver Surgery, Medical University of Warsaw, 02-097 Warszawa, Poland. michu244@interia.pl.
Michał
M
Zawadzki
Department of General Transplant and Liver Surgery, Medical University of Warsaw, 02-097 Warszawa, Poland. marek.krawczyk@wum.edu.pl.
Marek
M
Krawczyk
Translation Medicine Group, Pomeranian Medical University, 70-111 Szczecin, Poland. p.milkiewicz@wp.pl.|Liver and Internal Medicine Unit, Medical University of Warsaw, 02-097 Warszawa, Poland. p.milkiewicz@wp.pl.
Piotr
P
Milkiewicz
D015209:Cholangitis, Sclerosing / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D056747:Immunomodulation; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008105:Liver Cirrhosis, Biliary / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000235:genetics* / Q000378:metabolism
C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D000071222:Suppressor of Cytokine Signaling 1 Protein
cholestatic liver disease; miR-155; suppressor of cytokine signaling 1 (SOCS1); vitamin D receptor