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Arthritis Res Ther. 2017 Sep 18;19(1):207. doi: 10.1186/s13075-017-1386-x.

Endoplasmic reticulum stress cooperates with Toll-like receptor ligation in driving activation of rheumatoid arthritis fibroblast-like synoviocytes.

Kabala PA1,2,3,4,5, Angiolilli C1,2,3,4,5, Yeremenko N2,3,4, Grabiec AM2,3,4,6, Giovannone B5,7, Pots D2,3,4, Radstake TR1,5, Baeten D8,9,10, Reedquist KA1,5.

Author information

1
Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
2
Department of Clinical Immunology and Rheumatology, Academic Medical Centre/University of Amsterdam, Amsterdam, The Netherlands.
3
Amsterdam Rheumatology and Immunology Center, Amsterdam, The Netherlands.
4
Department of Experimental Immunology, Academic Medical Centre/University of Amsterdam, Amsterdam, The Netherlands.
5
Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
6
Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
7
Division of Internal Medicine and Dermatology, Department of Dermatology/Allergology, University Medical Center Utrecht, Utrecht, The Netherlands.
8
Department of Clinical Immunology and Rheumatology, Academic Medical Centre/University of Amsterdam, Amsterdam, The Netherlands. d.l.baeten@amc.uva.nl.
9
Amsterdam Rheumatology and Immunology Center, Amsterdam, The Netherlands. d.l.baeten@amc.uva.nl.
10
Department of Experimental Immunology, Academic Medical Centre/University of Amsterdam, Amsterdam, The Netherlands. d.l.baeten@amc.uva.nl.

Abstract

BACKGROUND:

Endoplasmic reticulum (ER) stress has proinflammatory properties, and transgenic animal studies of rheumatoid arthritis (RA) indicate its relevance in the process of joint destruction. Because currently available studies are focused primarily on myeloid cells, we assessed how ER stress might affect the inflammatory responses of stromal cells in RA.

METHODS:

ER stress was induced in RA fibroblast-like synoviocytes (FLS), dermal fibroblasts, and macrophages with thapsigargin or tunicamycin alone or in combination with Toll-like receptor (TLR) ligands, and gene expression and messenger RNA (mRNA) stability was measured by quantitative polymerase chain reaction. Cellular viability was measured using cell death enzyme-linked immunosorbent assays and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, and signaling pathway activation was analyzed by immunoblotting.

RESULTS:

No cytotoxicity was observed in FLS exposed to thapsigargin, despite significant induction of ER stress markers. Screening of 84 proinflammatory genes revealed minor changes in their expression (fold change 90th percentile range 2.8-8.3) by thapsigargin alone, but the vast majority were hyperinduced during combined stimulation with thapsigargin and TLR ligands (35% greater than fivefold vs lipopolysaccharide alone). The synergistic response could not be explained by quantitative effects on nuclear factor-κB and mitogen-activated protein kinase pathways alone, but it was dependent on increased mRNA stability. mRNA stabilization was similarly enhanced by ER stress in dermal fibroblasts but not in macrophages, correlating with minimal cooperative effects on gene induction in macrophages.

CONCLUSIONS:

RA FLS are resistant to apoptosis induced by ER stress, but ER stress potentiates their activation by multiple TLR ligands. Interfering with downstream signaling pathway components of ER stress may be of therapeutic potential in the treatment of RA.

KEYWORDS:

Dermal fibroblasts; ER stress; Fibroblast-like synoviocytes; Inflammation; Macrophages; RNA stability; Rheumatoid arthritis

PMID:
28923079
PMCID:
PMC5604427
DOI:
10.1186/s13075-017-1386-x
[Indexed for MEDLINE]
Free PMC Article

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