title: Anti-citrullinated protein antibodies suppress let-7a expression in monocytes from patients with rheumatoid arthritis and facilitate the inflammatory responses in rheumatoid arthritis.
abstract: We hypothesized that anti-citrullinated protein antibodies (ACPAs) could affect the expression of miRNAs in monocytes and contribute to the inflammatory responses in rheumatoid arthritis (RA). The expression profiles of 270 human miRNAs, co-cultured with ACPAs or human immunoglobulin G (IgG), were analyzed using real-time polymerase chain reaction. Ten miRNAs exhibited differential expression in U937 cells after co-cultured with ACPAs compared with human IgG. The expression levels of these miRNAs were investigated in monocytes from 21 ACPA-positive RA patients and 13 controls. Among these miRNAs, the expression levels of let-7a was decreased in monocytes from ACPA-positive RA patients. The expression levels of let-7a showed a negative correlation with positivity of rheumatoid factor in patients sampled. We found that transfection of U937 cells with let-7a mimic suppressed K-Ras protein expression. In the ACPA-mediated signaling pathway, transfection of U937 cells with let-7a mimic suppressed the ACPA-enhanced phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (ERK1/2), and the expression and secretion of interleukin (IL)-1β. In conclusion, ACPA-mediated decreased let-7a expression in monocytes from ACPA-positive RA patients. Decreased let-7a expression was associated with the positivity of RF in ACPA-positive RA patients. The decreased expression of let-7a could facilitate the inflammatory pathway via enhanced ACPA-mediated phosphorylation of ERK1/2 and JNK and increased expression of IL-1β through an increase in the expression of Ras proteins.
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Ning-Sheng
authors.initials: NS
authors.lastname: Lai
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan.
authors.forename: Hui-Chun
authors.initials: HC
authors.lastname: Yu
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Chia-Li
authors.initials: CL
authors.lastname: Yu
authors.affiliation: Department of Medical Research, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan; Dalla Lana School of Public Health, University of Toronto, Ontario, Canada.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Koo
authors.affiliation: Department of Life Science and Institute of Molecular Biology, National Chung Cheng University, Chiayi, Taiwan.
authors.forename: Hsien-Bin
authors.initials: HB
authors.lastname: Huang
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan. Electronic address: e360187@yahoo.com.tw.
authors.forename: Ming-Chi
authors.initials: MC
authors.lastname: Lu
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D015415:Biomarkers; D002097:C-Reactive Protein; D016022:Case-Control Studies; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism*; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D012217:Rheumatoid Factor / Q000097:blood; D059467:Transcriptome; D020298:U937 Cells
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D017362:Cyclic AMP Response Element-Binding Protein; D007074:Immunoglobulin G; D053583:Interleukin-1beta; C117307:KRAS protein, human; D035683:MicroRNAs; D016755:Proto-Oncogene Proteins c-jun; C487931:mirnlet7 microRNA, human; D002097:C-Reactive Protein; D012217:Rheumatoid Factor; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Anti-citrullinated protein antibodies; MicroRNAs; Monocytes; Ras; Rheumatoid arthritis; let-7a