title: MicroRNA-155 contributes to enhanced resistance to apoptosis in monocytes from patients with rheumatoid arthritis.
abstract: Monocytes and macrophages are key mediators of inflammation in rheumatoid arthritis (RA). Their persistence at the inflammatory site is likely to contribute to immunopathology. We sought to characterise one mechanism by which persistence may be achieved: resistance to apoptosis and the role of mir-155 in this process. CD14+ monocytes from peripheral blood (PBM) and synovial fluid (SFM) of RA patients were found to be resistant to spontaneous apoptosis relative to PBM from healthy control (HC) individuals. RA SFM were also resistant to anti-Fas-mediated apoptosis and displayed a gene expression profile distinct from HC and RA PBM populations. Gene expression profiling analysis revealed that the differentially expressed genes in RA SFM vs. PBM were enriched for apoptosis-related genes and showed increased expression of the mir-155 precursor BIC. Following identification of potential mir-155 target transcripts by bioinformatic methods, we show increased levels of mature mir-155 expression in RA PBM and SFM vs. HC PBM and a corresponding decrease in SFM of two predicted mir-155-target mRNAs, apoptosis mediators CASP10 and APAF1. Using miR mimics, we demonstrate that mir-155 over-expression in healthy CD14+ cells conferred resistance to spontaneous apoptosis, but not Fas-induced death in these cells, and resulted in increased production of cytokines and chemokines. Collectively our data indicate that CD14+ cells from patients with RA show enhanced resistance to apoptosis, and suggest that an increase in mir-155 may partially contribute to this phenotype.
authors.affiliation: Centre for Inflammation Biology and Cancer Immunology, Division of Immunology, Infection and Inflammatory Disease, King's College London, United Kingdom.
authors.forename: Megha
authors.initials: M
authors.lastname: Rajasekhar
authors.affiliation: Centre for Inflammation Biology and Cancer Immunology, Division of Immunology, Infection and Inflammatory Disease, King's College London, United Kingdom.
authors.forename: Anton M
authors.initials: AM
authors.lastname: Olsson
authors.affiliation: Centre for Inflammation Biology and Cancer Immunology, Division of Immunology, Infection and Inflammatory Disease, King's College London, United Kingdom.
authors.forename: Kathryn J A
authors.initials: KJ
authors.lastname: Steel
authors.affiliation: Centre for Inflammation Biology and Cancer Immunology, Division of Immunology, Infection and Inflammatory Disease, King's College London, United Kingdom.
authors.forename: Mirella
authors.initials: M
authors.lastname: Georgouli
authors.affiliation: Centre for Inflammation Biology and Cancer Immunology, Division of Immunology, Infection and Inflammatory Disease, King's College London, United Kingdom.
authors.forename: Ushan
authors.initials: U
authors.lastname: Ranasinghe
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Christine
authors.initials: C
authors.lastname: Brender Read
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Klaus S
authors.initials: KS
authors.lastname: Frederiksen
authors.affiliation: Centre for Inflammation Biology and Cancer Immunology, Division of Immunology, Infection and Inflammatory Disease, King's College London, United Kingdom. Electronic address: leonie.taams@kcl.ac.uk.
authors.forename: Leonie S
authors.initials: LS
authors.lastname: Taams
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D015415:Biomarkers; D016022:Case-Control Studies; D002470:Cell Survival / Q000235:genetics; D019295:Computational Biology / Q000379:methods; D016207:Cytokines / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D063990:Gene Ontology; D006801:Humans; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism*; D010641:Phenotype; D034622:RNA Interference; D019014:fas Receptor / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D018950:Lipopolysaccharide Receptors; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D019014:fas Receptor
keywords: Cell death; MicroRNAs; Microarray; Mir-155; Monocyte; Synovial fluid