title: Role of laminin in matrix induction of macrophage urokinase-type plasminogen activator and 92-kDa metalloproteinase expression.
abstract: 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 metalloproteinase (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 beta1 chain of laminin had no effect on macrophage uPA expression, whereas SIKVAV, derived from alpha1 chain, stimulated uPA expression 20-fold. Preincubation of THP-1 monocytes with a monoclonal antibody directed against the alpha6 subunit of the alpha6beta1 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.
authors.affiliation: Department of Pathology, Cornell University Medical College, New York, New York 10021, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Khan
authors.forename: D J
authors.initials: DJ
authors.lastname: Falcone
mesh_terms: D000818:Animals; D015153:Blotting, Western; D017364:Collagenases / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D039121:Integrin alpha6beta1; D016023:Integrins / Q000378:metabolism; D007797:Laminin / Q000502:physiology*; D008264:Macrophages / Q000201:enzymology*; D020780:Matrix Metalloproteinase 9; D051379:Mice; D008970:Molecular Weight; D009842:Oligopeptides / Q000378:metabolism; D011480:Protease Inhibitors / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D017474:Receptors, Laminin / Q000378:metabolism; D015398:Signal Transduction; D019716:Tissue Inhibitor of Metalloproteinase-2; D019714:Tissue Inhibitor of Metalloproteinases; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
chemical_list: D006023:Glycoproteins; D039121:Integrin alpha6beta1; D016023:Integrins; D007797:Laminin; D009842:Oligopeptides; D011480:Protease Inhibitors; D011506:Proteins; D017474:Receptors, Laminin; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; C077583:seryl-isoleucyl-lysyl-valyl-alanyl-valinamide; D014568:Urokinase-Type Plasminogen Activator; D017364:Collagenases; D020780:Matrix Metalloproteinase 9