Role of laminin in matrix induction of macrophage urokinase-type plasminogen activator and 92-kDa metalloproteinase expression

Urokinase-type plasminogen activator (uPA) and 92-kDa matrix metalloproteinase (MMP-9) expression by RAW264.7 macrophages were up-regulated when plated on extracellular matrices, Collagen IV, fibronectin, and tenascin stimulated macrophages' MMP-9 expression, in contrast, laminin stimulated both uPA and MMP-9 expression in a dose- and time-dependent manner. The increase in macrophage uPA activity was preceded by an increase in their steady state levels of uPA mRNA. Laminin-induced uPA expression was most pronounced in RAW264.7 macrophages followed by THP-1 monocytes, J774A.1 macrophages, and bone marrow-derived macrophages. Neither laminin nor matrix induced alterations in THP-1 monocyte expression of plasminogen activator inhibitor, tissue inhibitor of metalloprotein ase (TIMP)-1 or TIMP-2. Synthetic laminin peptides were utilized to identify the laminin domain(s) responsible for induction of uPA expression, Peptides derived from the beta 1 chain of laminin had no effect on macrophage uPA expression, whereas SIKVAV, derived from alpha 1 chain, stimulated uPA expression 20-fold. Preincubation of THP-1 monocytes with a monoclonal antibody directed against the alpha 6 subunit of the alpha 6 beta 1 laminin receptor blocked matrix induction of uPA without affecting the induction of MMP-9. These results demonstrate that macrophage binding to laminin plays an important role in the regulation of their degradative phenotype via the up-regulation of uPA and MMP-9.