Protein tyrosine phosphatase nonreceptor type 2: an important regulator of lnterleukin-6 production in rheumatoid arthritis synovial fibroblasts

Borbala Aradi, Masaru Kato, Maria Filkova, Emmanuel Karouzakis, Kerstin Klein, Michael Scharl, Christoph Kolling, Beat A. Michel, Renate E. Gay, E. Búzás, Steffen Gay, Astrid Jüngel

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Abstract

OBJECTIVE: To investigate the role of protein tyrosine phosphatase nonreceptor type 2 (PTPN2) in the pathogenesis of rheumatoid arthritis (RA).

METHODS: Synovial tissue samples from patients with RA and patients with osteoarthritis (OA) were stained for PTPN2. Synovial fibroblasts were stimulated with tumor necrosis factor (TNF) and interleukin-1β (IL-1β), lipopolysaccharide (LPS), TRAIL, or thapsigargin. The expression of PTPN2 in synovial fibroblasts and peripheral blood mononuclear cells (PBMCs) was analyzed by real-time polymerase chain reaction and Western blotting. Cell death, the release of IL-6 and IL-8, and the induction of autophagy were analyzed after PTPN2 silencing. Methylated DNA immunoprecipitation analysis was used to evaluate DNA methylation-regulated gene expression of PTPN2.

RESULTS: PTPN2 was significantly overexpressed in synovial tissue samples from RA patients compared to OA patients. Patients receiving anti-TNF therapy showed significantly reduced staining for PTPN2 compared with patients treated with nonbiologic agents. PTPN2 expression was higher in RA synovial fibroblasts (RASFs) than in OASFs. This differential expression was not regulated by DNA methylation. PTPN2 was further up-regulated after stimulation with TNF, TNF combined with IL-1β, or LPS. There was no significant difference in basal PTPN2 expression in PBMCs from patients with RA, ankylosing spondylitis, or systemic lupus erythematosus or healthy controls. Most interestingly, PTPN2 silencing in RASFs 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 contributed to the increased apoptosis resistance of RASFs and increased autophagy.

CONCLUSION: This is the first study of PTPN2 in RASFs showing that PTPN2 regulates IL-6 production, cell death, and autophagy. Our findings indicate that PTPN2 is linked to the pathogenesis of RA via synovial fibroblasts.

Original languageEnglish
Pages (from-to)2624-2633
Number of pages10
JournalArthritis and Rheumatology
Volume67
Issue number10
DOIs
Publication statusPublished - Oct 1 2015

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Protein Tyrosine Phosphatases
Rheumatoid Arthritis
Fibroblasts
Autophagy
Tumor Necrosis Factor-alpha
Interleukin-6
DNA Methylation
Interleukin-8
Interleukin-1
Osteoarthritis
Lipopolysaccharides
Blood Cells
Cell Death
Thapsigargin
Ankylosing Spondylitis
Immunoprecipitation
Systemic Lupus Erythematosus

ASJC Scopus subject areas

  • Medicine(all)

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Protein tyrosine phosphatase nonreceptor type 2 : an important regulator of lnterleukin-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.; Búzás, E.; Gay, Steffen; Jüngel, Astrid.

In: Arthritis and Rheumatology, Vol. 67, No. 10, 01.10.2015, p. 2624-2633.

Research output: Contribution to journalArticle

Aradi, B, Kato, M, Filkova, M, Karouzakis, E, Klein, K, Scharl, M, Kolling, C, Michel, BA, Gay, RE, Búzás, E, Gay, S & Jüngel, A 2015, 'Protein tyrosine phosphatase nonreceptor type 2: an important regulator of lnterleukin-6 production in rheumatoid arthritis synovial fibroblasts', Arthritis and Rheumatology, vol. 67, no. 10, pp. 2624-2633. https://doi.org/10.1002/art.39256
Aradi, Borbala ; Kato, Masaru ; Filkova, Maria ; Karouzakis, Emmanuel ; Klein, Kerstin ; Scharl, Michael ; Kolling, Christoph ; Michel, Beat A. ; Gay, Renate E. ; Búzás, E. ; Gay, Steffen ; Jüngel, Astrid. / Protein tyrosine phosphatase nonreceptor type 2 : an important regulator of lnterleukin-6 production in rheumatoid arthritis synovial fibroblasts. In: Arthritis and Rheumatology. 2015 ; Vol. 67, No. 10. pp. 2624-2633.
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abstract = "OBJECTIVE: To investigate the role of protein tyrosine phosphatase nonreceptor type 2 (PTPN2) in the pathogenesis of rheumatoid arthritis (RA).METHODS: Synovial tissue samples from patients with RA and patients with osteoarthritis (OA) were stained for PTPN2. Synovial fibroblasts were stimulated with tumor necrosis factor (TNF) and interleukin-1β (IL-1β), lipopolysaccharide (LPS), TRAIL, or thapsigargin. The expression of PTPN2 in synovial fibroblasts and peripheral blood mononuclear cells (PBMCs) was analyzed by real-time polymerase chain reaction and Western blotting. Cell death, the release of IL-6 and IL-8, and the induction of autophagy were analyzed after PTPN2 silencing. Methylated DNA immunoprecipitation analysis was used to evaluate DNA methylation-regulated gene expression of PTPN2.RESULTS: PTPN2 was significantly overexpressed in synovial tissue samples from RA patients compared to OA patients. Patients receiving anti-TNF therapy showed significantly reduced staining for PTPN2 compared with patients treated with nonbiologic agents. PTPN2 expression was higher in RA synovial fibroblasts (RASFs) than in OASFs. This differential expression was not regulated by DNA methylation. PTPN2 was further up-regulated after stimulation with TNF, TNF combined with IL-1β, or LPS. There was no significant difference in basal PTPN2 expression in PBMCs from patients with RA, ankylosing spondylitis, or systemic lupus erythematosus or healthy controls. Most interestingly, PTPN2 silencing in RASFs 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 contributed to the increased apoptosis resistance of RASFs and increased autophagy.CONCLUSION: This is the first study of PTPN2 in RASFs showing that PTPN2 regulates IL-6 production, cell death, and autophagy. Our findings indicate that PTPN2 is linked to the pathogenesis of RA via synovial fibroblasts.",
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AU - Aradi, Borbala

AU - Kato, Masaru

AU - Filkova, Maria

AU - Karouzakis, Emmanuel

AU - Klein, Kerstin

AU - Scharl, Michael

AU - Kolling, Christoph

AU - Michel, Beat A.

AU - Gay, Renate E.

AU - Búzás, E.

AU - Gay, Steffen

AU - Jüngel, Astrid

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N2 - OBJECTIVE: To investigate the role of protein tyrosine phosphatase nonreceptor type 2 (PTPN2) in the pathogenesis of rheumatoid arthritis (RA).METHODS: Synovial tissue samples from patients with RA and patients with osteoarthritis (OA) were stained for PTPN2. Synovial fibroblasts were stimulated with tumor necrosis factor (TNF) and interleukin-1β (IL-1β), lipopolysaccharide (LPS), TRAIL, or thapsigargin. The expression of PTPN2 in synovial fibroblasts and peripheral blood mononuclear cells (PBMCs) was analyzed by real-time polymerase chain reaction and Western blotting. Cell death, the release of IL-6 and IL-8, and the induction of autophagy were analyzed after PTPN2 silencing. Methylated DNA immunoprecipitation analysis was used to evaluate DNA methylation-regulated gene expression of PTPN2.RESULTS: PTPN2 was significantly overexpressed in synovial tissue samples from RA patients compared to OA patients. Patients receiving anti-TNF therapy showed significantly reduced staining for PTPN2 compared with patients treated with nonbiologic agents. PTPN2 expression was higher in RA synovial fibroblasts (RASFs) than in OASFs. This differential expression was not regulated by DNA methylation. PTPN2 was further up-regulated after stimulation with TNF, TNF combined with IL-1β, or LPS. There was no significant difference in basal PTPN2 expression in PBMCs from patients with RA, ankylosing spondylitis, or systemic lupus erythematosus or healthy controls. Most interestingly, PTPN2 silencing in RASFs 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 contributed to the increased apoptosis resistance of RASFs and increased autophagy.CONCLUSION: This is the first study of PTPN2 in RASFs showing that PTPN2 regulates IL-6 production, cell death, and autophagy. Our findings indicate that PTPN2 is linked to the pathogenesis of RA via synovial fibroblasts.

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