The Interplay between Transcriptional Factors and MicroRNAs as an Important Factor for Th17/Treg Balance in RA Patients

Tomasz Kmiołek,Dominik Majewski,Ewa Walczuk,Andrzej Pawlik,Ewa Rzeszotarska,Agnieszka Paradowska-Gorycka,Pawel Piotr Jagodzinski,Ewa Kuca-Warnawin,Katarzyna Romanowska-Próchnicka,Barbara Stypinska,Anna Wajda

doi:10.3390/ijms21197169

Abstract

MicroRNAs regulate gene expression of transcriptional factors, which influence Th17/Treg (regulatory T cells) balance, establishing the molecular mechanism of genetic and epigenetic regulation of Treg and Th17 cells is crucial for understanding rheumatoid arthritis (RA) pathogenesis. The study goal was to understand the potential impact of the selected microRNAs expression profiles on Treg/Th17 cells frequency, RA phenotype, the expression profile of selected microRNAs, and their correlation with the expression profiles of selected transcriptional factors: SOCS1, SMAD3, SMAD4, STAT3, STAT5 in RA; we used osteoarthritis (OA) and healthy controls (HCs) as controls. The study was conducted on 14 RA and 11 OA patients, and 15 HCs. Treg/Th17 frequency was established by flow cytometry. Gene expression analysis was estimated by qPCR. We noticed correlations in RA Th17 cells between miR-26 and SMAD3, STAT3, SOCS1; and miR-155 and STAT3—and in RA Treg cells between miR-26 and SOCS1; miR-31, -155 and SMAD3; and miR-155 and SMAD4. In RA Tregs, we found a negative correlation between miR-26, -126 and STAT5a. The expression level of miR-31 in Th17 cells from RA patients with DAS28 ≤ 5.1 is higher and that for miR-24 is greater in Tregs from patients with DAS28 > 5.1. MiR-146a in Tregs is higher in rheumatoid factor (RF) positive RA patients.

Highlights

Rheumatoid arthritis (RA) is one of the most widespread inflammatory diseases that affect the immune system
Our association study revealed correlations of expression levels in Treg cells obtained from rheumatoid arthritis (RA) patients between miR-26 and Suppressor of cytokine signaling 1 (SOCS1), miR-31 and SMAD3, miR-155 and SMAD3, SMAD4
The present study showed that RA Treg cells have a negative correlation between STAT5a and miR-26 level as well as between miR-126 and STAT5a level

Summary

Introduction

Rheumatoid arthritis (RA) is one of the most widespread inflammatory diseases that affect the immune system. The most common symptoms are pain, joint swelling, and disability. In RA occurs proliferative synovitis leading to bone and cartilage destruction. The inflamed synovium contains synovial fibroblasts, macrophages, and T cells that secrete inflammatory cytokines. In RA occurs undue immune response of T cells. CD4+ T cells contain helper T cells (Th cells) and they stimulate the immune responses as well as regulatory T cells (Treg cells) that control these responses. Th cells include Th1, Th2, and Th17 cells subsets. RA is characterized by an imbalance in Th17/Treg, and Th17 is more activated than Treg [1]

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