Altered microRNA expression profile with miR-146a upregulation in CD4+ T cells from patients with rheumatoid arthritis.
BACKGROUND
Increasing evidence indicates that microRNAs (miRNAs) play a critical role in the pathogenesis of inflammatory diseases. The aim of the study was to investigate the expression pattern and function of miRNAs in CD4+ T cells from patients with rheumatoid arthritis (RA).


METHODS
The expression profile of miRNAs in CD4+ T cells from synovial fluid (SF) and peripheral blood of 33 RA patients was determined by microarray assay and validated by qRT-PCR analysis. The correlation between altered expression of miRNAs and cytokine levels was determined by linear regression analysis. The role of miR-146a overexpression in regulating T cell apoptosis was evaluated by flow cytometry. A genome-wide gene expression analysis was further performed to identify miR-146a-regulated genes in T cells.


RESULTS
miRNA expression profile analysis revealed that miR-146a expression was significantly upregulated while miR-363 and miR-498 were downregulated in CD4+ T cells of RA patients. The level of miR-146a expression was positively correlated with levels of tumor necrosis factor-alpha (TNF-alpha), and in vitro studies showed TNF-alpha upregulated miR-146a expression in T cells. Moreover, miR-146a overexpression was found to suppress Jurkat T cell apoptosis. Finally, transcriptome analysis of miR-146a overexpression in T cells identified Fas associated factor 1 (FAF1) as a miR-146a-regulated gene, which was critically involved in modulating T cell apoptosis.


CONCLUSIONS
We have detected increased miR-146a in CD4+ T cells of RA patients and its close correlation with TNF-alpha levels. Our findings that miR-146a overexpression suppresses T cell apoptosis indicate a role of miR-146a in RA pathogenesis and provide potential novel therapeutic targets.
Li
Jingyi
J
Institute of Immunology, PLA, Third Military Medical University, 30# Gaotanyan Street, District Shipingba, Chongqing 400038, PR China.
Wan
Ying
Y
Guo
Qiuye
Q
Zou
Liyun
L
Zhang
Jinyu
J
Fang
Yongfei
Y
Zhang
Jingbo
J
Zhang
Jinjun
J
Fu
Xiaolan
X
Liu
Hongli
H
Lu
Liwei
L
Wu
Yuzhang
Y
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D016014:Linear Models; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D013582:Synovial Fluid / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; C490780:FAF1 protein, human; C542542:MIRN146 microRNA, human; C574861:MIRN363 microRNA, human; D035683:MicroRNAs; D014409:Tumor Necrosis Factor-alpha
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