FK506 suppresses the stimulation of matrix metalloproteinase 13 synthesis by interleukin-1β in rheumatoid synovial fibroblasts
Introduction
Rheumatoid arthritis (RA) is characterized by the overgrowth of synovium and subsequent articular cartilage destruction [1]. Various immunosuppressive agents have been shown to be effective in the treatment of RA [2]. FK506, a macrolide immunosuppressant via lymphockine signal transduction pathway, also has efficacy in the treatment of severe and refractory RA [3], [4], [5], [6], [7]. FK506 binds to its cytoplasmic receptor, the FK506-binding protein (FK-BP), and the resulting complexes inactivate calcineurin, a pivotal phosphatase for T cell signaling [8]. Calcineurin binds to nuclear factor of activated T cells (NF-AT) resulting in dephosphorylation and subsequent translocation to the nucleus for cytokine genes expression. Therefore, FK506 acts directly on the T lymphocytes to prevent cytokines gene expression [9]. Although T cell-mediated immune activation appears to play an important role in the pathogenesis of RA [10], overproduction of matrix metalloproteinases (MMPs) from synoviocytes also contributes to the joint destruction of RA [11]. A recent study has showed that FK506 suppressed the activation of mitogen-activated protein kinase (MAPK) in myocardium during allograft rejection [12]. MAPK is involved in inflammation as well as in T cell signaling [13]. Of the three MAPK families (ERK, JNK, p38), JNK is likely to play a central role in RA, since this MAPK activates a key transcription factor, AP-1, which is involved in MMPs gene expression [14]. Aware of the importance of MMPs in RA, we investigated the effects of FK506 on MAPK activation and MMPs synthesis by synovial fibroblasts obtained from RA patients.
Section snippets
Reagents
FK506 was provided by Fujisawa Pharmaceutical Co. (Osaka, Japan). FK506 was resolved by ethanol and the final concentration of ethanol in culture condition was below 0.001%. Human recombinant IL-1β (1.5 × 108 U/mg) was kindly provided by Dainihon Chemical Co. (Osaka, Japan). Mouse anti-human matrix metalloproteinase 13 (MMP-13) antibodies, which react with pro-MMP-13 and activated form of MMP-13, were obtained from Fuji Chemical Co. (Takaoka, Japan). All other reagents were purchased from Sigma
Results
As shown in Fig. 1A, MMP-2 was constitutively produced from unstimulated rheumatoid synovial cells. Stimulation of synovial cells with IL-1β slightly increased the secretion MMP-2. The addition of FK506 to the synovial cell culture did not significantly affect this IL-1β-induced increased MMP-2 secretion from the rheumatoid synovial cells. IL-1β stimulation induced the MMP-3 production from rheumatoid synovial cells. High concentrations of FK506 slightly inhibited this IL-1β-induced MMP-3
Discussion
FK506 is a potent immunosuppressant that can be used to prevent and treat acute rejection or graft-versus-host disease (GVHD) after transplantations [15]. Recent studies suggest that FK506 affects a broad spectrum of inflammatory mediators and possesses anti-inflammatory properties [16]. The efficacy of this agent in treating refractory rheumatoid arthritis was also demonstrated [3], [4], [5], [6], [7]. Inhibition of calcineurin by FK506 leads to interference with the translocation to the
Acknowledgement
This work was supported by Fujisawa Pharmaceutical Corporation (Osaka, Japan).
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