Enhanced expression of miR-21 and miR-150 is a feature of anti-mitochondrial antibody-negative primary biliary cholangitis

Urszula Wasik,Piotr Milkiewicz,Agnieszka Kempinska-Podhorodecka,Dimitrios P Bogdanos,Malgorzata Milkiewicz

doi:10.1186/s10020-019-0130-1

Abstract

Background & AimsAnti-mitochondrial-autoantibodies (AMA) remain a hallmark of Primary Biliary Cholangitis (PBC) however approximately 10% of patients test negative for these antibodies. They do not differ in terms of biochemistry or clinical presentation from AMA positive ones. Epigenetics play a key role in immune signalling. Two microRNAs (miRs), namely, miR-21 and miR-150 are known to be involved in liver inflammation and fibrosis. The expression of those two microRNAs and their downstream targets were analyze in the context of AMA-status and the stage of liver fibrosis.MethodsThe relative levels of miR-21 and miR-150 and their target genes: cMyb, RAS-guanyl-releasing protein-1(RASGRP1), and DNA-methyltransferase-1(DNMT1) were determined by Real-Time PCR in serum, liver tissue and peripheral blood mononuclear cells (PBMCs) of patients with PBC.ResultsSerum expressions of miR-21 and miR-150 were significantly enhanced in AMA-negative patients, and they inversely correlated with disease-specific AMA titers in PBS patients. In PBMCs, an increased expression of miR-21 correlated with decreased levels of RASGRP1 and DNMT1 mRNAs whereas, the level of miR-150 remained comparable to controls; and cMyb mRNA was downregulated. In cirrhotic livers, the level of miR-21 was unchanged while miR-150 expression was increased.ConclusionThis study convincingly report, that AMA-negative PBC is characterized by notable alternations of miR-21 and miR-150 and their downstream targets compared to AMA-positive patients underlining their possible importance in the induction of the disease and its progression to fibrosis.

Highlights

Primary biliary cholangitis (PBC) is a chronic, autoimmune, cholestatic liver disease that may lead to liver failure
In peripheral blood mononuclear cells (PBMCs), an increased expression of miR-21 correlated with decreased levels of RAS guanyl-releasing protein 1 (RASGRP1) and DNA methyltransferase 1 (DNMT1) mRNAs whereas, the level of miR-150 remained comparable to controls; and cMyb mRNA was downregulated
This study convincingly report, that AMA-negative Primary Biliary Cholangitis (PBC) is characterized by notable alternations of miR21 and miR-150 and their downstream targets compared to AMA-positive patients underlining their possible importance in the induction of the disease and its progression to fibrosis

Summary

Introduction

Primary biliary cholangitis (PBC) is a chronic, autoimmune, cholestatic liver disease that may lead to liver failure. In dominant-negative TGF-β receptor II mice, which spontaneously develop an autoimmune cholangitis similar to human PBC the T cell dysregulation is associated with upregulation of the key inflammatory miR-21 (Ando et al 2013), and in close relevance to the present study, miR-21 has showed consistent and significant down-regulation in B cells of PBC patients from stage I to stage III of PBC (Wang et al 2017). Anti-mitochondrial-autoantibodies (AMA) remain a hallmark of Primary Biliary Cholangitis (PBC) approximately 10% of patients test negative for these antibodies. They do not differ in terms of biochemistry or clinical presentation from AMA positive ones. The expression of those two microRNAs and their downstream targets were analyze in the context of AMA-status and the stage of liver fibrosis

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Results

Discussion

Conclusion