Nuclear factor kappaB/p50 activates an element in the distal matrix metalloproteinase 1 promoter in interleukin-1beta-stimulated synovial fibroblasts.
OBJECTIVE
To determine how interleukin-1 (IL-1), through activation of collagenase 1 (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 kappaB (NF-kappaB).


CONCLUSIONS
These studies demonstrate, for the first time, a role for NF-kappaB in the induction of MMP-1, and suggest a mechanism of NF-kappaB-mediated cartilage degradation in rheumatoid arthritis.
Vincenti
M P
MP
Department of Medicine, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Coon
C I
CI
Brinckerhoff
C E
CE
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D017364:Collagenases / Q000235:genetics*; D003238:Connective Tissue / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology*; D020781:Matrix Metalloproteinase 1; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000502:physiology*; D011817:Rabbits; D013583:Synovial Membrane / Q000166:cytology* / Q000201:enzymology; D018808:Transcription Factor AP-1 / Q000276:immunology / Q000378:metabolism; D015533:Transcriptional Activation / Q000276:immunology
D004268:DNA-Binding Proteins; D007375:Interleukin-1; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D017364:Collagenases; D020781:Matrix Metalloproteinase 1