Nuclear factor κB p50 activates an element in the distal matrix metalloproteinase 1 promoter in interleukin-1β-stimulated synovial fibroblasts

Objective. To determine how interleukin-1 (IL-1), through activation of collagenase I (matrix metalloproteinase 1 [MMP-1]) transcription in synovial fibroblasts, contributes to cartilage degradation in rheumatoid arthritis. Methods. Primary rabbit synovial fibroblasts were transiently transfected with; MMP-1 promoter/ luciferase constructs, and promoter activity in response to IL-1 was assessed. A minimal IL-1-response element was defined and used to evaluate DNA binding proteins by electrophoretic mobility shift assay and in situ ultraviolet crosslinking assay. Results. Transcriptional activation of the MMP-1 gene by IL-1 in rabbit synovial fibroblasts required a dorsal-like element, which was located at nucleotide (nt) -3,029, as well as an activator protein 1 site at nt -77. Importantly, an IL-1-induced DNA binding activity that was specific for the dorsal-like element contained the p50 subunit of nuclear factor kappa B (NF-kappa B), Conclusion. These studies demonstrate, for the first time, a role for NF-kappa B in the induction of MMP-1, and suggest a mechanism of NF-kappa B-mediated cartilage degradation in rheumatoid arthritis.