title: IL-4 inhibition of IL-1 induced Matrix metalloproteinase-3 (MMP-3) expression in human fibroblasts involves decreased AP-1 activation via negative crosstalk involving of Jun N-terminal kinase (JNK).
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Philadelphia College of Osteopathic Medicine, 4170 City Avenue, Philadelphia, PA 19131, USA.
authors.forename: Mariah
authors.initials: M
authors.lastname: Chambers
authors.forename: Garrett
authors.initials: G
authors.lastname: Kirkpatrick
authors.forename: Michel
authors.initials: M
authors.lastname: Evans
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Gorski
authors.forename: Sara
authors.initials: S
authors.lastname: Foster
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Borghaei
mesh_terms: D001665:Binding Sites; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D052816:Foreskin / Q000166:cytology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism*; D010518:Periodontitis / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D055503:Protein Multimerization; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: C064269:FOSB protein, human; D007375:Interleukin-1; C581727:JunB protein, human; C559371:JunD protein, human; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D015847:Interleukin-4; D048055:Mitogen-Activated Protein Kinase 8; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1