MicroRNA-17 Suppresses TNF-α Signaling by Interfering with TRAF2 and cIAP2 Association in Rheumatoid Arthritis Synovial Fibroblasts

Nahid Akhtar; Anil Kumar Singh; Salahuddin Ahmed

doi:10.4049/jimmunol.1600360

Back

MicroRNA-17 Suppresses TNF-α Signaling by Interfering with TRAF2 and cIAP2 Association in Rheumatoid Arthritis Synovial Fibroblasts

Journal article

Open access

Peer reviewed

MicroRNA-17 Suppresses TNF-α Signaling by Interfering with TRAF2 and cIAP2 Association in Rheumatoid Arthritis Synovial Fibroblasts

Nahid Akhtar, Anil Kumar Singh and Salahuddin Ahmed

The Journal of immunology (1950), Vol.197(6), pp.2219-2228

09/15/2016

DOI: https://doi.org/10.4049/jimmunol.1600360

Handle:

https://hdl.handle.net/2376/116574

PMCID: PMC5010933

PMID: 27534557

Files and links (1)

url

https://doi.org/10.4049/jimmunol.1600360View

Published (Version of record) Open

Abstract

MAP Kinase Signaling System - physiology

Signal Transduction

Arthritis, Rheumatoid - etiology

Humans

Cells, Cultured

Ubiquitin - metabolism

Synovial Membrane - immunology

Matrix Metalloproteinase 1 - biosynthesis

Baculoviral IAP Repeat-Containing 3 Protein

TNF Receptor-Associated Factor 2 - physiology

Ubiquitin-Protein Ligases - physiology

Inhibitor of Apoptosis Proteins - physiology

Tumor Necrosis Factor-alpha - pharmacology

NF-kappa B - physiology

Fibroblasts - immunology

MicroRNAs - physiology

Arthritis, Rheumatoid - immunology

Cytokines - biosynthesis

STAT3 Transcription Factor - metabolism

TNF-α is a major cytokine implicated in rheumatoid arthritis (RA), and its expression is regulated at the transcriptional and posttranscriptional levels. However, the impact of changes in microRNA expression on posttranslational processes involved in TNF-α signaling networks is not well defined in RA. In this study, we evaluated the effect of miR-17, a member of the miR-17-92 cluster, on the TNF-α signaling pathway in human RA synovial fibroblasts (SFs). We demonstrated that miR-17 expression was significantly low in RA serum, SFs, and synovial tissues, as well as in the serum and joints of adjuvant-induced arthritis rats. RNA-sequencing analysis showed modulation of 664 genes by pre-miR-17 in human RA SFs. Ingenuity pathway analysis of RNA-sequencing data identified the ubiquitin proteasome system in the TNF-α signaling pathway as a primary target of miR-17. Western blot analysis confirmed the reduction in TRAF2, cIAP1, cIAP2, USP2, and PSMD13 expression by miR-17 in TNF-α-stimulated RA SFs. Immunoprecipitation assays showed that miR-17 restoration increased the K48-linked polyubiquitination of TRAF2, cIAP1, and cIAP2 in TNF-α-stimulated RA SFs. Thus, destabilization of TRAF2 by miR-17 reduced the ability of TRAF2 to associate with cIAP2, resulting in the downregulation of TNF-α-induced NF-κBp65, c-Jun, and STAT3 nuclear translocation and the production of IL-6, IL-8, MMP-1, and MMP-13 in human RA SFs. In conclusion, this study provides evidence for the role of miR-17 as a negative regulator of TNF-α signaling by modulating the protein ubiquitin processes in RA SFs.

Metrics

Details

Title: MicroRNA-17 Suppresses TNF-α Signaling by Interfering with TRAF2 and cIAP2 Association in Rheumatoid Arthritis Synovial Fibroblasts
Creators: Nahid Akhtar - Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA 99210
Anil Kumar Singh - Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA 99210
Salahuddin Ahmed - Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA 99210 salah.ahmed@wsu.edu
Publication Details: The Journal of immunology (1950), Vol.197(6), pp.2219-2228
Academic Unit: Pharmaceutical Sciences, Department of
Publisher: United States
Grant note: R01 AR063104 / NIAMS NIH HHS
Identifiers: 99900547323301842
Language: English
Resource Type: Journal article