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Interleukin‐1 beta induction of matrix metalloproteinase‐1 transcription in chondrocytes requires ERK‐dependent activation of CCAAT enhancer‐binding protein‐beta
Author(s) -
Raymond Lauren,
Eck Sarah,
Mollmark Jessica,
Hays Ezra,
Tomek Ivan,
Kantor Stephen,
Elliott Sarah,
Vincenti Matthew
Publication year - 2006
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.20608
Subject(s) - ccaat enhancer binding proteins , mapk/erk pathway , microbiology and biotechnology , transcription factor , enhancer , signal transduction , biology , phosphorylation , kinase , promoter , chemistry , gene expression , dna binding protein , biochemistry , gene
Interleukin‐1 beta (IL‐1β) is a central mediator of inflammation and connective tissue destruction in rheumatoid arthritis. IL‐1β activates articular chondrocytes to produce matrix metalloproteinase‐1 (MMP‐1), an enzyme capable of dismantling the collagen scaffold of articular cartilage. To define the transcription factors and signaling intermediates that activate MMP‐1 transcription in chondrocytes, we performed transient transfection of MMP‐1 promoter constructs followed by reporter assays. These studies identified an IL‐1β‐responsive region of the human MMP‐1 promoter that contains a consensus CCAAT enhancer‐binding protein (C/EBP) binding site. Deletion of this site reduced overall transcriptional activity of the MMP‐1 promoter, as well as decreased fold induction by IL‐1β. IL‐1β stimulation of chondrocytes increased binding of C/EBP‐β to the MMP‐1 C/EBP site. Extracellular signal regulated kinase (ERK) pathway‐dependent phosphorylation of C/EBP‐β on threonine 235 activates this transcription factor. Here we show that IL‐1β stimulation of chondrocytes induced phosphorylation of C/EBP‐β on threonine 235, and that the ERK pathway inhibitor PD98059 reduced this phosphorylation. We further show that PD98059 reduces IL‐1β‐induced MMP‐1 mRNA expression in chondrocytes. Moreover, inhibition of the ERK pathway by expression of dominant‐negative forms of ERK1 and ERK2 impaired the ability of IL‐1β to transactivate the MMP‐1 promoter. Our findings demonstrate a novel role for C/EBP‐β in IL‐1β‐induced connective tissue disease and define a new nuclear target for the ERK pathway in MMP‐1 gene activation. J. Cell. Physiol. © 2006 Wiley‐Liss, Inc.