FK506 suppresses the stimulation of matrix metalloproteinase 13 synthesis by interleukin-1β in rheumatoid synovial fibroblasts

The aim of this study was to determine whether FK506, which has been shown to be effective for the treatment of refractory RA, affects the synthesis of matrix metalloproteinases (MMPs) in rheumatoid synovial fibroblasts. Synovial fibroblasts isolated from rheumatoid synovium were incubated in 6-well culture plates for 24 h with FK506 and interleukin-1β, alone and in combination. Samples of supernatants were assayed by ELISA or immunoblottings using anti-MMP-13 specific antibodies. In addition, synovial fibroblasts pretreated with FK506 were stimulated with IL-1β for 10 min and cellular lysates were subjected to anti-phospho-specific mitogen-activated protein kinase (MAPK). Unstimulated synovial fibroblasts produced low levels of MMP-3 and 13. IL-1β-induced substantial output of these MMPs into cell supernatants. FK506 had no detectable effects on IL-1β-induced MMP-2 induction. FK506, however, significantly suppressed MMP-13 production from IL-1β-stimulated synovial fibroblasts. FK506 also prevented IL-1β-stimulated JNK activation and transcriptional activation of AP-1 in these cells. Our results indicate that FK506 is capable of regulating MMP-13 synthesis via JNK pathway in rheumatoid synonvium.