title: 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.
authors: Unité de Formation et Recherche de Sciences Pharmaceutiques, Université de Strasbourg, Illkirch Cedex, France.
authors: Lucas
authors: L
authors: Philippe
authors: Ghada
authors: G
authors: Alsaleh
authors: Guillaume
authors: G
authors: Suffert
authors: Alain
authors: A
authors: Meyer
authors: Philippe
authors: P
authors: Georgel
authors: Jean
authors: J
authors: Sibilia
authors: Dominique
authors: D
authors: Wachsmann
authors: Sébastien
authors: S
authors: Pfeffer
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis / Q000276:immunology; D035683:MicroRNAs / Q000276:immunology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000276:immunology; D013583:Synovial Membrane / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis / Q000276:immunology*
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; C549214:MIRN19A microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3