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

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-kappa B 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-kappa B and AP-1 inhibitor. Methods: Cultured synoviocytes were stimulated with sulforaphane (SFN) with or without TNF-alpha pre-treatment. NF-kappa B, 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-alpha-stimulated synoviocytes. SFN did not reduce MMP-3 and MMP-9 activity or expression significantly. Interestingly, we demonstrated that SFN has opposing effects on nave and TNF-alpha-stimulated synoviocytes. In nave cells, SFN activated the cytoprotective transcription factor Nrf2. In marked contrast to this, SFN induced apoptosis in TNF-alpha-pre-stimulated synoviocytes. Conclusions: We were able to show that SFN treatment acts contrary on nave and inflammatory synoviocytes. SFN induces the cytoprotective transcription factor Nrf2 in nave 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.