{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T19:11:18Z","timestamp":1789067478093,"version":"build-2803163510"},"reference-count":48,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2017,1,29]],"date-time":"2017-01-29T00:00:00Z","timestamp":1485648000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Centre in Poland","award":["no.2011\/02\/A\/NZ5\/00321 and no.2015\/17\/B\/NZ5\/02541"],"award-info":[{"award-number":["no.2011\/02\/A\/NZ5\/00321 and no.2015\/17\/B\/NZ5\/02541"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms18020289","type":"journal-article","created":{"date-parts":[[2017,1,30]],"date-time":"2017-01-30T11:36:30Z","timestamp":1485776190000},"page":"289","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["Decreased Expression of Vitamin D Receptor Affects an Immune Response in Primary Biliary Cholangitis via the VDR-miRNA155-SOCS1 Pathway"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7513-8640","authenticated-orcid":false,"given":"Agnieszka","family":"Kempinska-Podhorodecka","sequence":"first","affiliation":[{"name":"Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata","family":"Milkiewicz","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urszula","family":"Wasik","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4977-9679","authenticated-orcid":false,"given":"Joanna","family":"Ligocka","sequence":"additional","affiliation":[{"name":"Department of General Transplant and Liver Surgery, Medical University of Warsaw, 02-097 Warszawa, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micha\u0142","family":"Zawadzki","sequence":"additional","affiliation":[{"name":"Department of General Transplant and Liver Surgery, Medical University of Warsaw, 02-097 Warszawa, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marek","family":"Krawczyk","sequence":"additional","affiliation":[{"name":"Department of General Transplant and Liver Surgery, Medical University of Warsaw, 02-097 Warszawa, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Milkiewicz","sequence":"additional","affiliation":[{"name":"Translation Medicine Group, Pomeranian Medical University, 70-111 Szczecin, Poland"},{"name":"Liver and Internal Medicine Unit, Medical University of Warsaw, 02-097 Warszawa, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1056\/NEJMra043898","article-title":"Primary biliary cirrhosis","volume":"353","author":"Kaplan","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1136\/gut.2007.122150","article-title":"Pathogenesis of primary biliary cirrhosis","volume":"84","author":"Jones","year":"2008","journal-title":"Postgrad. Med. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.hepres.2003.09.003","article-title":"Cellular immune response in primary biliary cirrhosis","volume":"28","author":"Kita","year":"2004","journal-title":"Hepatol. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.jaut.2008.11.001","article-title":"Hepatic IL-17 responses in human and murine primary biliary cirrhosis","volume":"32","author":"Lan","year":"2009","journal-title":"J. Autoimmun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1002\/hep.26979","article-title":"IL-12\/Th1 and IL-23\/Th17 biliary microenvironment in primary biliary cirrhosis: implications for therapy","volume":"59","author":"Yang","year":"2014","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1002\/hep.21123","article-title":"Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis","volume":"43","author":"Lan","year":"2006","journal-title":"Hepatology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2502","DOI":"10.3390\/nu5072502","article-title":"Vitamin D and immune function","volume":"5","author":"Prietl","year":"2013","journal-title":"Nutrients"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1152\/physrev.1998.78.4.1193","article-title":"Current understanding of the molecular actions of vitamin D","volume":"78","author":"Jones","year":"1998","journal-title":"Physiol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1038\/nature05563","article-title":"Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells","volume":"445","author":"Zheng","year":"2007","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1210\/er.2008-0004","article-title":"Vitamin D and human health: lessons from vitamin D receptor null mice","volume":"29","author":"Bouillon","year":"2008","journal-title":"Endocr. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2685","DOI":"10.1210\/me.2005-0106","article-title":"Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes","volume":"19","author":"Wang","year":"2005","journal-title":"Mol. Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/j.jocn.2012.10.005","article-title":"Vitamin D and multiple sclerosis","volume":"20","author":"Hewer","year":"2013","journal-title":"J. Clin. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1177\/2042018812471070","article-title":"Vitamin D and rheumatoid arthritis","volume":"3","author":"Athanassiou","year":"2012","journal-title":"Ther. Adv. Endocrinol. Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0092-8674(04)00045-5","article-title":"MicroRNAs: Genomics, biogenesis, mechanism, and function","volume":"116","author":"Bartel","year":"2004","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.immuni.2010.09.009","article-title":"MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development","volume":"33","author":"Kahn","year":"2010","journal-title":"Immunity"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/S1074-7613(03)00240-1","article-title":"Suppressor of cytokine signaling-1 is essential for suppressing dendritic cell activation and systemic autoimmunity","volume":"19","author":"Hanada","year":"2003","journal-title":"Immunity"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"20","DOI":"10.3389\/fimmu.2012.00020","article-title":"SOCS, Inflammation, and Autoimmunity","volume":"3","author":"Yoshimura","year":"2012","journal-title":"Front. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/S0092-8674(00)80048-3","article-title":"SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality","volume":"98","author":"Marine","year":"1999","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3746","DOI":"10.4049\/jimmunol.180.6.3746","article-title":"Loss of suppressor of cytokine signaling 1 in helper T cells leads to defective Th17 differentiation by enhancing antagonistic effects of IFN-gamma on STAT3 and Smads","volume":"180","author":"Tanaka","year":"2008","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1093\/intimm\/dxq469","article-title":"SOCS1 regulates type I\/type II NKT cell balance by regulating IFN\u03b3 signaling","volume":"23","author":"Hashimoto","year":"2011","journal-title":"Int. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/gene.2011.89","article-title":"Association of primary biliary cirrhosis with variants in the CLEC16A, SOCS1, SPIB and SIAE immunomodulatory genes","volume":"13","author":"Hirschfield","year":"2012","journal-title":"Genes Immun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3687","DOI":"10.4049\/jimmunol.1203273","article-title":"1,25-Dihydroxyvitamin D promotes negative feedback regulation of TLR signaling via targeting microRNA-155-SOCS1 in macrophages","volume":"190","author":"Chen","year":"2013","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1053\/jhep.2002.30084","article-title":"Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis","volume":"35","author":"Vogel","year":"2002","journal-title":"Hepatology"},{"key":"ref_24","first-page":"408723","article-title":"Vitamin D receptor polymorphisms predispose to primary biliary cirrhosis and severity of the disease in polish population","volume":"2012","author":"Wunsch","year":"2012","journal-title":"Gastroenterol. Res. Pract."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1053\/jhep.2003.50176","article-title":"The normal liver harbors the vitamin D nuclear receptor in nonparenchymal and biliary epithelial cells","volume":"37","author":"Demers","year":"2003","journal-title":"Hepatology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1002\/hep.25930","article-title":"Liver vitamin D receptor, CYP2R1, and CYP27A1 expression: relationship with liver histology and vitamin D3 levels in patients with nonalcoholic steatohepatitis or hepatitis C virus","volume":"56","author":"Barchetta","year":"2012","journal-title":"Hepatology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/nri2708","article-title":"Physiological and pathological roles for microRNAs in the immune system","volume":"10","author":"Rao","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2624","DOI":"10.1007\/s10620-009-1069-9","article-title":"Prevalence of vitamin D deficiency in chronic liver disease","volume":"55","author":"Arteh","year":"2010","journal-title":"Dig. Dis. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s12026-014-8594-0","article-title":"Vitamin D in primary biliary cirrhosis, a plausible marker of advanced disease","volume":"61","author":"Kopilov","year":"2015","journal-title":"Immunol. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1093\/intimm\/dxn033","article-title":"Suppressor of cytokine signaling-1 ameliorates dextran sulfate sodium-induced colitis in mice","volume":"20","author":"Horino","year":"2008","journal-title":"Int. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1002\/hep.22214","article-title":"Suppressor of cytokine signaling 1 protects mice against concanavalin A-induced hepatitis by inhibiting apoptosis","volume":"47","author":"Torisu","year":"2008","journal-title":"Hepatology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7423","DOI":"10.4049\/jimmunol.180.11.7423","article-title":"Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocytes","volume":"180","author":"Pene","year":"2008","journal-title":"J. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1111\/j.1365-2249.2009.03898.x","article-title":"Imbalance between T helper type 17 and T regulatory cells in patients with primary biliary cirrhosis: The serum cytokine profile and peripheral cell population","volume":"156","author":"Rong","year":"2009","journal-title":"Clin. Exp. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/j.autrev.2012.05.004","article-title":"Th17 and regulatory T lymphocytes in primary biliary cirrhosis and systemic sclerosis as models of autoimmune fibrotic diseases","volume":"12","author":"Fenoglio","year":"2012","journal-title":"Autoimmun. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.cyto.2013.07.005","article-title":"Increased IL-23 and IL-17 expression by peripheral blood cells of patients with primary biliary cirrhosis","volume":"64","author":"Qian","year":"2013","journal-title":"Cytokine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1016\/j.immuni.2011.02.021","article-title":"Transcription factor Smad-independent T helper 17 cell induction by transforming-growth factor-beta is mediated by suppression of eomesodermin","volume":"34","author":"Ichiyama","year":"2011","journal-title":"Immunity"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1002\/hep.26447","article-title":"Increased T helper type 17 response to pathogen stimulation in patients with primary sclerosing cholangitis","volume":"58","author":"Katt","year":"2013","journal-title":"Hepatology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1126\/science.1142331","article-title":"Emerging challenges in regulatory T cell function and biology","volume":"317","author":"Sakaguchi","year":"2007","journal-title":"Science"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1146\/annurev.immunol.21.120601.141122","article-title":"Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses","volume":"22","author":"Sakaguchi","year":"2004","journal-title":"Annu. Rev. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/cmi.2015.12","article-title":"Regulatory T cells turn pathogenic","volume":"12","author":"Guo","year":"2015","journal-title":"Cell. Mol. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2055","DOI":"10.1084\/jem.20110428","article-title":"SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-\u03b3 and IL-17A production","volume":"208","author":"Takahashi","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1517\/14712598.7.11.1689","article-title":"T-regulatory lymphocytes and chronic viral hepatitis","volume":"7","author":"Rushbrook","year":"2007","journal-title":"Expert. Opin. Biol. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1002\/hep.20644","article-title":"Compromised lymphocytes infiltrate hepatocellular carcinoma: The role of T-regulatory cells","volume":"41","author":"Unitt","year":"2005","journal-title":"Hepatology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.jaut.2010.06.004","article-title":"Phenotypical and functional alterations of CD8 regulatory T cells in primary biliary cirrhosis","volume":"35","author":"Bernuzzi","year":"2010","journal-title":"J. Autoimmun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.4049\/jimmunol.1001171","article-title":"Cbl-b(\u2212\/\u2212) T cells demonstrate in vivo resistance to regulatory T cells but a context-dependent resistance to TGF-\u03b2","volume":"185","author":"Adams","year":"2010","journal-title":"J. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.immuni.2008.11.010","article-title":"Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein","volume":"30","author":"Lu","year":"2009","journal-title":"Immunity"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"14395","DOI":"10.1073\/pnas.95.24.14395","article-title":"Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1","volume":"95","author":"Starr","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1111\/liv.12030","article-title":"Activation of FoxO3a\/Bim axis in patients with Primary Biliary Cirrhosis","volume":"33","author":"Kopycinska","year":"2013","journal-title":"Liver Int."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/2\/289\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:27:14Z","timestamp":1760207234000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/2\/289"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,1,29]]},"references-count":48,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2017,2]]}},"alternative-id":["ijms18020289"],"URL":"https:\/\/doi.org\/10.3390\/ijms18020289","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,1,29]]}}}