Monocyte membrane type 1-matrix metalloproteinase. Prostaglandin-dependent regulation and role in metalloproteinase-2 activation

• Published in: The Journal of biological chemistry 2001-06, Vol.276 (22), p.19027-19032
• Main Authors: Shankavaram, U T, Lai, W C, Netzel-Arnett, S, Mangan, P R, Ardans, J A, Caterina, N, Stetler-Stevenson, W G, Birkedal-Hansen, H, Wahl, L M
• Format: Article
• Language: English
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; Adenylyl Cyclases - metabolism; Adenylyl Cyclases - pharmacology; Blotting, Western; Bucladesine - pharmacology; Cells, Cultured; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Cyclic AMP-Dependent Protein Kinases - pharmacology; Dinoprostone - metabolism; Enzyme Activation; Enzyme Inhibitors - pharmacology; Fibroblasts - metabolism; Flow Cytometry; Humans; Indomethacin - pharmacology; Lipopolysaccharides - pharmacology; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinases, Membrane-Associated; Metalloendopeptidases - chemistry; Metalloendopeptidases - physiology; Monocytes - enzymology; Monocytes - metabolism; prostaglandins; Prostaglandins - metabolism; RNA - metabolism; Tissue Inhibitor of Metalloproteinase-2 - metabolism; Tissue Inhibitor of Metalloproteinase-2 - physiology
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M009562200

Membrane type 1-matrix metalloproteinase (MT1-MMP)-mediated activation of MMP-2 is thought to be important in the proteolysis of extracellular matrix in pathological events in which monocytes/macrophages are found. Here we report on the induction and regulation of human monocyte MT1-MMP and its role in MMP-2 activation. Activation of monocytes by lipopolysaccharide resulted in the induction of MT1-MMP mRNA and protein that was suppressed by inhibitors of prostaglandin synthesis (indomethacin), adenylyl cyclase (SQ 22536), and protein kinase A (Rp-cAMPs). Suppression of MT1-MMP by indomethacin and SQ 22536 was reversed by prostaglandin E(2) and dibutyryl cyclic AMP, respectively, demonstrating that induction of monocyte MT1-MMP is regulated through a prostaglandin-cAMP pathway. Functional analysis revealed that pro-MMP-2 in the supernatants from human bone marrow stromal fibroblasts, normal male-derived fibroblasts and melanoma cells (A2058) was converted to active MMP-2 when cultured with activated but not control monocytes. Antibodies against MT1-MMP blocked the activation of MMP-2. Tissue inhibitor of metalloproteinase-2 regulation of MMP-2 activation was shown through the addition of varying amounts of recombinant tissue inhibitor of metalloproteinase-2 with pro-MMP-2 to MT1-MMP-expressing monocytes. These findings demonstrate that activated monocytes express functionally active MT1-MMP that may play a significant role in the activation of MMP-2 produced by other cells and as such influence developmental and pathological conditions.