Transforming growth factor-β1 inhibits cytokine-mediated induction of human metalloelastase in macrophages

M. W. Feinberg, M. K. Jain, F. Werner, Nicholas E.S. Sibinga, P. Wiesel, H. Wang, J. N. Topper, M. A. Perrella, M. E. Lee

Research output: Contribution to journalArticle

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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-2) 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-1β, tumor necrosis factor-α, 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-β1 (TGF-β1) 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-β1 depended on signaling; through an AP-1 site at -81 base pairs. Moreover, the inhibitory effect of TGF-β1 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-β1 suggests that TGF-β1, acting via Smad3, may promote plaque stability.

Original languageEnglish (US)
Pages (from-to)25766-25773
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number33
DOIs
StatePublished - Aug 18 2000
Externally publishedYes

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Matrix Metalloproteinase 12
Macrophages
Transforming Growth Factors
Cytokines
Atherosclerotic Plaques
Matrix Metalloproteinases
Extracellular Matrix
Atherosclerosis
Intercellular Signaling Peptides and Proteins
Electrophoretic mobility
Messenger RNA
Macrophage Colony-Stimulating Factor
Matrix Metalloproteinase 2
Transcription Factor AP-1
Electrophoretic Mobility Shift Assay
Substrate Specificity
human MMP12 protein
Interleukin-1
Base Pairing
Vascular Endothelial Growth Factor A

ASJC Scopus subject areas

  • Biochemistry

Cite this

Transforming growth factor-β1 inhibits cytokine-mediated induction of human metalloelastase in macrophages. / Feinberg, M. W.; Jain, M. K.; Werner, F.; Sibinga, Nicholas E.S.; Wiesel, P.; Wang, H.; Topper, J. N.; Perrella, M. A.; Lee, M. E.

In: Journal of Biological Chemistry, Vol. 275, No. 33, 18.08.2000, p. 25766-25773.

Research output: Contribution to journalArticle

Feinberg, MW, Jain, MK, Werner, F, Sibinga, NES, Wiesel, P, Wang, H, Topper, JN, Perrella, MA & Lee, ME 2000, 'Transforming growth factor-β1 inhibits cytokine-mediated induction of human metalloelastase in macrophages', Journal of Biological Chemistry, vol. 275, no. 33, pp. 25766-25773. https://doi.org/10.1074/jbc.M002664200
Feinberg, M. W. ; Jain, M. K. ; Werner, F. ; Sibinga, Nicholas E.S. ; Wiesel, P. ; Wang, H. ; Topper, J. N. ; Perrella, M. A. ; Lee, M. E. / Transforming growth factor-β1 inhibits cytokine-mediated induction of human metalloelastase in macrophages. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 33. pp. 25766-25773.
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