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Protein Tyrosine Phosphatase Nonreceptor Type 2 (PTPN2), an Important Regulator of IL-6 Production in Rheumatoid Arthritis Synovial Fibroblasts


Aradi, Borbala; Kato, Masaru; Filkova, Maria; Karouzakis, Emmanuel; Klein, Kerstin; Scharl, Michael; Kolling, Christoph; Michel, Beat A; Gay, Renate E; Buzas, Edit I; Gay, Steffen; Jüngel, Astrid (2015). Protein Tyrosine Phosphatase Nonreceptor Type 2 (PTPN2), an Important Regulator of IL-6 Production in Rheumatoid Arthritis Synovial Fibroblasts. Arthritis and Rheumatology, 67(10):2624-2633.

Abstract

Objective This article is protected by copyright. All rights reserved. Methods Synovial tissues from RA and osteoarthritis (OA) were stained for PTPN2. Synovial fibroblasts (SF), were stimulated with TNF and IL1β, LPS, TRAIL or thapsigargin. Expression of PTPN2 in SF or PBMCs was analyzed by Real-time PCR and Western blotting. Cell death, the release of IL-6 and IL-8 and the induction of autophagy were analyzed after PTPN2 silencing. MeDIP analysis was used to check DNA methylation-regulated gene expression of PTPN2. Results PTPN2 was significantly overexpressed in synovial tissues of RA compared to OA. Patients treated with anti-TNF therapy showed significantly reduced staining for PTPN2 compared with patients treated with non-biologics. In RASF, PTPN2 expression was higher compared to OASF. This differential expression is not regulated by DNA methylation. PTPN2 was further upregulated after stimulation with TNF, TNF combined with IL1β and LPS. There was no significant difference in basal PTPN2 expression in PBMCs from patients with RA, ankylosing spondylitis, systemic lupus erythematosus and healthy controls. Most interestingly, PTPN2 silencing in RASF significantly increased the production of the inflammatory cytokine IL-6 but did not affect levels of IL-8. Moreover, functional analysis showed that high PTPN2 levels contribute to the increased apoptosis resistance of RASF and increased autophagy. Conclusion This is the first study on PTPN2 in RASF showing that PTPN2 regulates IL-6 production, cell death and autophagy. This indicates that PTPN2 is linked to the pathogenesis of RA via synovial fibroblasts. This article is protected by copyright. All rights reserved.

Abstract

Objective This article is protected by copyright. All rights reserved. Methods Synovial tissues from RA and osteoarthritis (OA) were stained for PTPN2. Synovial fibroblasts (SF), were stimulated with TNF and IL1β, LPS, TRAIL or thapsigargin. Expression of PTPN2 in SF or PBMCs was analyzed by Real-time PCR and Western blotting. Cell death, the release of IL-6 and IL-8 and the induction of autophagy were analyzed after PTPN2 silencing. MeDIP analysis was used to check DNA methylation-regulated gene expression of PTPN2. Results PTPN2 was significantly overexpressed in synovial tissues of RA compared to OA. Patients treated with anti-TNF therapy showed significantly reduced staining for PTPN2 compared with patients treated with non-biologics. In RASF, PTPN2 expression was higher compared to OASF. This differential expression is not regulated by DNA methylation. PTPN2 was further upregulated after stimulation with TNF, TNF combined with IL1β and LPS. There was no significant difference in basal PTPN2 expression in PBMCs from patients with RA, ankylosing spondylitis, systemic lupus erythematosus and healthy controls. Most interestingly, PTPN2 silencing in RASF significantly increased the production of the inflammatory cytokine IL-6 but did not affect levels of IL-8. Moreover, functional analysis showed that high PTPN2 levels contribute to the increased apoptosis resistance of RASF and increased autophagy. Conclusion This is the first study on PTPN2 in RASF showing that PTPN2 regulates IL-6 production, cell death and autophagy. This indicates that PTPN2 is linked to the pathogenesis of RA via synovial fibroblasts. This article is protected by copyright. All rights reserved.

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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:610 Medicine & health
Language:English
Date:2 July 2015
Deposited On:06 Aug 2015 12:47
Last Modified:08 Dec 2017 13:42
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:2326-5205
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1002/art.39256
PubMed ID:26139109

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