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

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

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142 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Feinberg, M. W., Jain, M. K., Werner, F., Sibinga, N. E. S., Wiesel, P., Wang, H., Topper, J. N., Perrella, M. A., & Lee, M. E. (2000). Transforming growth factor-β1 inhibits cytokine-mediated induction of human metalloelastase in macrophages. Journal of Biological Chemistry, 275(33), 25766-25773. https://doi.org/10.1074/jbc.M002664200