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Open Access Highly Accessed Research article

Sulforaphane has opposing effects on TNF-alpha stimulated and unstimulated synoviocytes

Athanassios Fragoulis1*, Jendrik Laufs1, Susanna Müller1, Ulf Soppa2, Stephanie Siegl2, Lucy Kathleen Reiss2, Mersedeh Tohidnezhad1, Christian Rosen1, Klaus Tenbrock3, Deike Varoga4, Sebastian Lippross4, Thomas Pufe1 and Christoph Jan Wruck1

Author Affiliations

1 Department of Anatomy and Cell Biology, University Hospital Aachen, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany

2 Institute of Pharmacology and Toxicology, University Hospital Aachen, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany

3 Department of Paediatric and Adolescent Medicine, University Hospital Aachen, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany

4 Department of Trauma Surgery, University Hospital of Schleswig-Holstein UK-SH, Campus Kiel, Arnold-Heller Strasse 3, 24105 Kiel, Germany

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Arthritis Research & Therapy 2012, 14:R220  doi:10.1186/ar4059

Published: 27 October 2012

Abstract

Introduction

Rheumatoid arthritis (RA) is characterized by progressive inflammation associated with rampantly proliferating synoviocytes and joint destruction due to oxidative stress. Recently, we described nuclear factor erythroid 2-related factor 2 (Nrf2) as a major requirement for limiting cartilage destruction. NF-κB and AP-1 are the main transcription factors triggering the inflammatory progression in RA. We used sulforaphane, an isothiocyanate, which is both an Nrf2 inducer and a NF-κB and AP-1 inhibitor.

Methods

Cultured synoviocytes were stimulated with sulforaphane (SFN) with or without TNF-α pre-treatment. NF-κB, AP-1, and Nrf2 activation was investigated via dual luciferase reporter gene assays. Matrix metalloproteinases (MMPs) were measured via zymography and luminex technique. Cytokine levels were detected using ELISA. Cell viability, apoptosis and caspase activity were studied. Cell proliferation was analysed by real-time cell analysis.

Results

SFN treatment decreased inflammation and proliferation dose-dependently in TNF-α-stimulated synoviocytes. SFN did not reduce MMP-3 and MMP-9 activity or expression significantly. Interestingly, we demonstrated that SFN has opposing effects on naïve and TNF-α-stimulated synoviocytes. In naïve cells, SFN activated the cytoprotective transcription factor Nrf2. In marked contrast to this, SFN induced apoptosis in TNF-α-pre-stimulated synoviocytes.

Conclusions

We were able to show that SFN treatment acts contrary on naïve and inflammatory synoviocytes. SFN induces the cytoprotective transcription factor Nrf2 in naïve synoviocytes, whereas it induces apoptosis in inflamed synoviocytes. These findings indicate that the use of sulforaphane might be considered as an adjunctive therapeutic strategy to combat inflammation, pannus formation, and cartilage destruction in RA.