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The TNFα-induced miR-18a activates rheumatoid arthritis synovial fibroblasts through a feedback loop in NF-κB signaling


Trenkmann, Michelle; Brock, Matthias; Gay, Renate E; Michel, Beat A; Gay, Steffen; Huber, Lars C (2013). The TNFα-induced miR-18a activates rheumatoid arthritis synovial fibroblasts through a feedback loop in NF-κB signaling. Arthritis & Rheumatism, 65(4):916-927.

Abstract

Objective: To elucidate whether the microRNA (miRNA) cluster miR-17-92 contributes to the activated phenotype of rheumatoid arthritis synovial fibroblasts (RASF). Methods: RASF were stimulated with tumor necrosis factor alpha (TNFα? and expression and regulation of the miR-17-92 cluster were studied using quantitative real-time PCR (qPCR) and promoter activity assays. RASF were transfected with single precursor molecules of miRNAs from miR-17-92 and the expression of matrix-degrading enzymes and cytokines was measured by qPCR and enzyme-linked immunosorbent assay. Potential miRNA targets were identified by computational prediction and validated using reporter gene assays and Western blot. The activity of NF-κB signaling was determined by reporter gene assay. Results: We found that TNFα induces the expression of miR-17-92 in RASF in a nuclear factor kappa B (NF-κB)-dependent manner. Transfection of RASF with precursor molecules of single members of miR-17-92 revealed significantly increased expression levels of matrix-degrading enzymes, proinflammatory cytokines and chemokines in pre-miR-18a-transfected RASF. Using reporter gene assays we identified the NF-κB pathway inhibitor TNFα-induced protein 3 (TNFAIP3) as a new target of miR-18a. In consequence, pre-miR-18a-transfected RASF showed stronger activation of NF-κB signaling, both constitutively and in response to TNFα-stimulation. Conclusion: Our data suggest that the miR-17-92-derived miR-18a contributes to cartilage destruction and chronic inflammation in the joint through a positive feedback loop in NF-κB signaling with concomitant upregulation of matrix-degrading enzymes and inflammatory mediators in RASF. © 2012 American College of Rheumatology.

Abstract

Objective: To elucidate whether the microRNA (miRNA) cluster miR-17-92 contributes to the activated phenotype of rheumatoid arthritis synovial fibroblasts (RASF). Methods: RASF were stimulated with tumor necrosis factor alpha (TNFα? and expression and regulation of the miR-17-92 cluster were studied using quantitative real-time PCR (qPCR) and promoter activity assays. RASF were transfected with single precursor molecules of miRNAs from miR-17-92 and the expression of matrix-degrading enzymes and cytokines was measured by qPCR and enzyme-linked immunosorbent assay. Potential miRNA targets were identified by computational prediction and validated using reporter gene assays and Western blot. The activity of NF-κB signaling was determined by reporter gene assay. Results: We found that TNFα induces the expression of miR-17-92 in RASF in a nuclear factor kappa B (NF-κB)-dependent manner. Transfection of RASF with precursor molecules of single members of miR-17-92 revealed significantly increased expression levels of matrix-degrading enzymes, proinflammatory cytokines and chemokines in pre-miR-18a-transfected RASF. Using reporter gene assays we identified the NF-κB pathway inhibitor TNFα-induced protein 3 (TNFAIP3) as a new target of miR-18a. In consequence, pre-miR-18a-transfected RASF showed stronger activation of NF-κB signaling, both constitutively and in response to TNFα-stimulation. Conclusion: Our data suggest that the miR-17-92-derived miR-18a contributes to cartilage destruction and chronic inflammation in the joint through a positive feedback loop in NF-κB signaling with concomitant upregulation of matrix-degrading enzymes and inflammatory mediators in RASF. © 2012 American College of Rheumatology.

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26 citations in Web of Science®
27 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine
04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2013
Deposited On:13 Mar 2013 16:47
Last Modified:05 Apr 2016 16:41
Publisher:Wiley-Blackwell
ISSN:0004-3591
Publisher DOI:https://doi.org/10.1002/art.37834
PubMed ID:23280137

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