title: Transforming growth factor-beta 1 inhibits cytokine-mediated induction of human metalloelastase in macrophages.
abstract: Matrix metalloproteinases (MMP) have been identified in vulnerable areas of atherosclerotic plaques and may contribute to plaque instability through extracellular matrix degradation. Human metalloelastase (MMP-12) is a macrophage-specific MMP with broad substrate specificity and is capable of degrading proteins found in the extracellular matrix of atheromas. Despite its potential importance, little is known about the regulation of MMP-12 expression in the context of atherosclerosis. In this study, we report that in human peripheral blood-derived macrophages, MMP-12 mRNA was markedly up-regulated by several pro-atherosclerotic cytokines and growth factors including interleukin-1beta, tumor necrosis factor-alpha, macrophage colony-stimulating factor, vascular endothelial growth factor, and platelet-derived growth factor-BB. In contrast, the pleiotropic anti-inflammatory growth factor transforming growth factor-beta1 (TGF-beta1) inhibited cytokine-mediated induction of MMP-12 mRNA, protein, and enzymatic activity. Analyses of MMP-12 promoter through transient transfections and electrophoretic mobility shift assays indicated that both its induction by cytokines and its inhibition by TGF-beta1 depended on signaling through an AP-1 site at -81 base pairs. Moreover, the inhibitory effect of TGF-beta1 on MMP-12 was dependent on Smad3. Taken together, MMP-12 is induced by several factors implicated in atherosclerosis. The inhibition of MMP-12 expression by TGF-beta1 suggests that TGF-beta1, acting via Smad3, may promote plaque stability.
authors.affiliation: Program of Developmental Cardiovascular Biology, the Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. Feinberg@cvlab.bwh.harvard.edu
authors.forename: M W
authors.initials: MW
authors.lastname: Feinberg
authors.forename: M K
authors.initials: MK
authors.lastname: Jain
authors.forename: F
authors.initials: F
authors.lastname: Werner
authors.forename: N E
authors.initials: NE
authors.lastname: Sibinga
authors.forename: P
authors.initials: P
authors.lastname: Wiesel
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: J N
authors.initials: JN
authors.lastname: Topper
authors.forename: M A
authors.initials: MA
authors.lastname: Perrella
authors.forename: M E
authors.initials: ME
authors.lastname: Lee
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism; D001665:Binding Sites; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004790:Enzyme Induction; D005799:Genes, Dominant; D017930:Genes, Reporter; D006801:Humans; D008264:Macrophages / Q000201:enzymology*; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000201:enzymology; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051900:Smad3 Protein; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D008666:Metalloendopeptidases; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12