TLR2 Expression Is Regulated by MicroRNA miR-19 in Rheumatoid Fibroblast-like Synoviocytes

Abstract

Resident cells, such as fibroblast-like synoviocytes (FLS), play a crucial role in rheumatoid arthritis (RA). They are implicated in the inflammatory response and play a key role in osteoarticular destruction. Moreover, RA FLS spread RA to unaffected joints. Pathogen-associated molecular patterns and damage-associated molecular patterns have been found to activate RA FLS by interacting with pattern recognition receptors, such as TLR. RA FLS express a large number of TLR, and TLR2 was demonstrated to be involved in RA inflammation. Because microRNA have emerged as important controllers of TLR expression and signaling, the aim of this study was to evaluate their potential involvement in the control of TLR2 expression by RA FLS. We first showed that Tlr2 expression is strongly upregulated in RA FLS in response to TLR2 ligands. Using a microRNA microarray analysis, we identified one miRNA in activated RA FLS, miR-19b, which was downregulated and predicted to target Tlr2 mRNA. Downregulation of miR-19b and miR-19a, which belongs to the same cluster, was confirmed by real-time quantitative PCR. Transfection of RA FLS with miR-19a/b mimics decreased TLR2 protein expression. In parallel, we found that both IL-6 and matrix metalloproteinase 3 secretion was significantly downregulated in activated FLS transfected with either mimic. Moreover, using a luciferase assay, we showed that miR-19a/b directly target Tlr2 mRNA. Taken together, our data point toward an important role for miR-19a/b in the regulation of IL-6 and matrix metalloproteinase 3 release by controlling TLR2 expression, as well as provide evidence that miR-19a/b can act as negative regulators of inflammation in humans.

Effect of miR-19a and miR-21 on the JAK/STAT signaling pathway in the peripheral blood mononuclear cells of patients with systemic juvenile idiopathic arthritis

“…Philippe et al (30) reported that toll-like receptor 2 (TLR2) was highly expressed in the synovial cells of RA induced by LPS. In an miRNA chip, miR-19a/b was demonstrated to be downregulated in RA synovial cells, and miR-19a mimics were demonstrated to decrease the expression levels of TLR2, IL-6 and MMP3.…”

miR-19b promotes tumor growth and metastasis via targeting TP53

“…It is well known that a perfect match between the target sequence and a "seed region" at nucleotides 2-8 is critically important for the target predication. Actually, both miR-19a and miR-19b share a number of targeted genes, such as ATXN1, CUL5, and TLR2 (Lee et al 2008;Philippe et al 2012;Xu et al 2012). However, miR-19a, but not miR-19b, was found to target TNF-α (Liu et al 2010), whereas mainly miR-19b was involved in the NF-κB pathway by targeting RNF11 (Gantier et al 2012).…”

MicroRNAs in the regulation of TLR and RIG-I pathways

“…75 However, in fibroblast-like synoviocytes from rheumatoid arthritis patients, miR-19a/b was decreased in response to TLR2 ligands and was responsible for the upregulated TLR2 expression in these cells. 76 miR-19a/b mimics reduced TLR2 level and thus inhibited TLR2-triggered cytokine production. Although these data suggest that miRNAs regulate TLR expression, it is more effective, economical and common in humans cells to regulate downstream TLR signal molecules by miRNAs than by completely shutting down the TLR signal pathway by eliminating receptor expression.…”