Abstract
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.
Highlights
Primary biliary cholangitis (PBC) is characterized by the immune-mediated destruction of small intrahepatic bile ducts and portal inflammation that may lead to the progressive development of liver fibrosis and liver failure [1]
Biological effects of vitamin D are mediated through the vitamin D receptor (VDR), an NR1I family receptor with transcription factor activities, which forms a heterodimer with Retinoid X receptor (RXR) and binds to DNA response elements in target genes [10]
Expression of the VDR gene was substantially suppressed in livers of non-cirrhotic and cirrhotic patients with PBC when compared to controls (53% reduction, p = 0.02, and 51% reduction p = 0.02, respectively)
Summary
Primary biliary cholangitis (PBC) is characterized by the immune-mediated destruction of small intrahepatic bile ducts and portal inflammation that may lead to the progressive development of liver fibrosis and liver failure [1]. Vitamin D is a well-known immune modulator of both innate and adaptive immunities It acts by inhibition of T cell activation and proliferation, suppression of pro-inflammatory cytokines, or induction of differentiation of forkhead family transcriptional regulator box P3 (FOXP3)-positive regulatory T cells [7,8,9]. These vitamin D–dependent modulations essentially lessen autoreactivity. In the present study we attempted to clarify a function of the VDR-regulated signaling pathway in liver tissue and peripheral blood mononuclear cells (PBMC) of patients with PBC and PSC
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