Transforming growth factor-ss 1 inhibits cytokine-mediated induction of human metalloelastase in macrophages

Matrix metalloproteinases (MMP) have been identified in vulnerable areas of atherosclerotic plaques and may contribute to plaque instability through e xtracellular matrix degradation. Human metalloelastase (MMP-12) is a macrop hage-specific MMP with broad substrate specificity and is capable of degrad ing proteins found in the extracellular matrix of atheromas, Despite its po tential importance, little is known about the regulation of MMP-12 expressi on in the context of atherosclerosis. In this study, we report that in huma n peripheral blood-derived macrophages, MMP-12 mRNA was markedly upregulate d by several pro-atherosclerotic cytokines and growth factors including int erleukin-1 beta, tumor necrosis factor-alpha, macrophage colony-stimulating factor, vascular endothelial growth factor, and platelet-derived growth fa ctor-BB. In contrast, the pleiotropic anti-inflammatory growth factor trans forming growth factor-beta 1 (TGF-beta 1) inhibited cytokine-mediated induc tion of MMP-12 mRNA, protein, and enzymatic activity. Analyses of MMP-12 pr omoter through transient transfections and electrophoretic mobility shift a ssays indicated that both its induction by cytokines and its inhibition by TGF-beta 1 depended on signaling through an AP-1 site at -81 base pairs. Mo reover, the inhibitory effect of TGF-beta 1 on MMP-12 was dependent on Smad 3. Taken together, MMP-12 is induced by several factors implicated in ather osclerosis. The inhibition of MMP-12 expression by TGF-beta 1 suggests that TGF-beta 1, acting via Smad3, may promote plaque stability.