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

Membrane type 1-matrix metalloproteinase (MT1-MMP)-mediated activation of M MP-2 is thought to be important in the proteolysis of extracellular matrix in pathological events in which monocytes/macrophages are found. Here we re port on the induction and regulation of human monocyte MT1-MMP and its role in MMP-2 activation. Activation of monocytes by lipopolysaccharide resulte d in the induction of MT1-MMP mRNA and protein that was suppressed by inhib itors 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, and dibutyryl cyclic AMP, res pectively, demonstrating that induction of monocyte MT1-MMP is regulated th rough a prostaglandin-cAMP pathway. Functional analysis revealed that pro-M MP-2 in the supernatants from human bone marrow stromal fibroblasts, normal male-derived fibroblasts and melanoma cells (A2058) was converted to activ e MMP-2 when cultured with activated but not control monocytes, Antibodies against MT1-MMP blocked the activation of MMP-2. Tissue inhibitor of metall oproteinase-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 a s such influence developmental and pathological conditions.