Decreased Expression of Vitamin D Receptor Affects an Immune Response in Primary Biliary Cholangitis via the VDR-miRNA155-SOCS1 Pathway

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.

The expression and methylation status of vitamin D receptor gene in Behcet's disease

“…The importance of VDR expression in the development of other diseases is becoming increasingly apparent. Kempinska-Podhorodecka et al 20 showed that expression of the VDR gene in PBMCs of patients with primary biliary cirrhosis and primary sclerosing cholangitis is decreased. 20 Regarding the low expression of VDR gene in patients with BD, we could not find any significant association between methylation pattern and the expression level of VDR gene.…”

“…Kempinska-Podhorodecka et al 20 showed that expression of the VDR gene in PBMCs of patients with primary biliary cirrhosis and primary sclerosing cholangitis is decreased. 20 Regarding the low expression of VDR gene in patients with BD, we could not find any significant association between methylation pattern and the expression level of VDR gene. More and larger studies on the molecular level are needed to determine the lower expression of VDR gene in patients with BD.…”

“…Binding of 1,25(OH)2D3 to the intracellular VDR regulates more than 900 genes . The ubiquitously expression of VDR gene by almost all tissues and cells of body provides a biological basis for widespread functions of VDR and its ligands . The VDR encoding gene is located on the long arm of chromosome12 (12q13.11), contain eight introns, nine exons with four potential promoter regions (Exons1a, 1c, and 1d of the VDR are well conserved, while1b, 1e, and 1f show low homology) .…”

Pathophysiological Role and Therapeutic Implications of Vitamin D in Autoimmunity: Focus on Chronic Autoimmune Diseases

“…The implication of vitamin D-VDR signaling pathway has been studied in the PBC and PSC pathogenic process. Kempinska-Podhorodecka et al found that in PBC livers, either cirrhotic or not, there is a significant impairment in VDR expression, resulting in enhancement of non-coding miR155 and consequent SOCS1 reduction, which probably interferes with the negative feedback on pro-inflammatory cytokines response [275]. Actually, VDR is also an important receptor for ursodeoxycholic acid (UDCA) inducing cathelicidin expression in biliary epithelial cells [243]; it also mediates many epigenetic effects, which contribute to the reduction of pro-inflammatory cytokines synthesis [276].…”

Primary biliary cholangitis: A tale of epigenetically-induced secretory failure?

“…MiR-155, which is related to immune cell activation mainly through direct targeting of suppressor of cytokine signalling 1 (SOCS1), a well-known antagonist of inflammation, was also found to be overexpressed in PBC livers. 124 Finally, miR-34a and miR-132 were shown to be increased in the liver of cirrhotic patients with PBC when compared to healthy individuals, 125 which might be related with oxidative stress by direct targeting NRF2, and thus triggering disease progression.…”