Nuclear factor ?B/p50 activates an element in the distal matrix metalloproteinase 1 promoter in interleukin-1?-stimulated synovial fibroblasts

Abstract

Objective. To determine how interleukin-1 (IL-1), through activation of collagenase 1 (matrix metalloproteinase 1 [MMP-I]) 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 KB (NF-KB).Conclusion. These studies demonstrate, for the first time, a role for NF-KB in the induction of MMP-1, and suggest a mechanism of NF-KB-mediated cartilage degradation in rheumatoid arthritis.Rheumatoid arthritis (RA) is a severe, debilitating disease that is characterized

The myxoid liposarcoma FUS-DDIT3 fusion oncoprotein deregulates NF-κB target genes by interaction with NFKBIZ

“…In this study, we report that the MMP1 and LCN2 genes encoding matrix metalloproteinase 1 and lipocalin 2 (a cofactor for MMP9), both involved in extracellular matrix remodeling, are strongly expressed in FUS-DDIT3 carrying cell lines. MMP1 is reported to be regulated by NF-kB through a distal promoter element (Vincenti et al, 1998) and LCN2 has been reported to be transcriptionally controlled by NFKBIZ (Oikawa et al, 2006). These findings are supported by our experiments with an inducible NFKBIZ expression vector showing that the mRNA levels of LCN2, but not MMP1, are significantly raised by the nuclear expression of NFKBIZ.…”

“…IL8, IL6 and LCN2 are transcriptional targets of NFKBIZ In addition to IL8, MMP1 has also been shown to be regulated by the NF-kB system, and both IL6 and LCN2 have been reported to be downstream targets of NFKBIZ (Vincenti et al, 1998;Motoyama et al, 2005;Oikawa et al, 2006). To test whether these genes were transcriptionally controlled by NFKBIZ in our system, we used a tamoxifen-regulated vector system (Littlewood et al, 1995).…”

NF-κB and the immune response

“…NF-kB has also been implicated in the response to leukotrienes, which like prostaglandins are short-lived paracrine effectors, although it is unclear whether this represents a direct signaling event. Finally, matrix metalloproteinases (MMPs) also are crucial mediators of local inflammation and leukocyte chemotaxis; and their expression is also regulated by NF-kB (Vincenti et al, 1998;Vincenti and Brinckerhoff, 2002;Lai et al, 2003).…”

A20 suppresses inflammatory responses and bone destruction in human fibroblast‐like synoviocytes and in mice with collagen‐induced arthritis

“…NF-B activation in FLS also contributes to the pathogenesis of RA by activating the transcription of a family of matrix metalloproteinases (MMPs) (6). The MMP family includes over 20 members that differentially mediate the degradation of each component of the extracellular matrix, including MMP-1 and MMP-3, which have been reported to be the major enzymes involved in tissue destruction.…”