Abstract
Matrix metalloproteinase-3 (MMP-3) over-expression is associated with tissue destruction in the context of chronic inflammation. Previous studies showed that IL-4 inhibits induction of MMP-3 by IL-1β, and suggested that AP-1 might be involved. Here we show that IL-1 induced binding of transcription factor AP-1 to the MMP-3 promoter consists primarily of c-Jun, JunB, and c-Fos and that binding of c-Jun and c-Fos is inhibited by the combination of cytokines while binding of Jun B is not. Mutation of the AP-1 site in the MMP-3 promoter decreased the ability of IL-4 to inhibit its transcription in transfected MG-63 cells. Western blotting showed that both cytokines activate Jun N-terminal kinase (JNK), but with somewhat different kinetics, and that activation of JNK by both cytokines individually is inhibited by the combination. These results indicate that IL-4 inhibition of MMP-3 expression is associated with reduction of IL-1 induced binding of active forms of the AP-1 dimer, while less active JunB-containing dimers remain, and suggest that these changes are associated with decreased activation of JNK.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Binding Sites
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Blotting, Western
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Cell Line, Tumor
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Enzyme Activation
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Fibroblasts / drug effects
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Fibroblasts / enzymology
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Fibroblasts / metabolism
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Foreskin / cytology
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Humans
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Interleukin-1 / pharmacology*
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Interleukin-4 / pharmacology*
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Male
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Matrix Metalloproteinase 1 / genetics
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Matrix Metalloproteinase 1 / metabolism
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Matrix Metalloproteinase 3 / genetics
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Matrix Metalloproteinase 3 / metabolism*
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Mitogen-Activated Protein Kinase 8 / genetics
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Mitogen-Activated Protein Kinase 8 / metabolism*
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Periodontitis / enzymology
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Periodontitis / metabolism
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Periodontitis / pathology
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Promoter Regions, Genetic
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Protein Binding
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Protein Multimerization
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Proto-Oncogene Proteins c-fos / genetics
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Proto-Oncogene Proteins c-fos / metabolism
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Proto-Oncogene Proteins c-jun / genetics
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Proto-Oncogene Proteins c-jun / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Transcription Factor AP-1 / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcriptional Activation
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Transfection
Substances
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FOSB protein, human
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Interleukin-1
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JunB protein, human
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JunD protein, human
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Proto-Oncogene Proteins c-fos
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Proto-Oncogene Proteins c-jun
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RNA, Messenger
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Transcription Factor AP-1
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Transcription Factors
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Interleukin-4
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Mitogen-Activated Protein Kinase 8
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MMP3 protein, human
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Matrix Metalloproteinase 3
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MMP1 protein, human
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Matrix Metalloproteinase 1