title: Transforming growth factor-beta differently regulates urokinase type plasminogen activator and matrix metalloproteinase-9 expression in mouse macrophages; analysis of intracellular signal transduction.
abstract: Transforming growth factor β (TGF-β) modulates capacity of macrophages to produce urokinase type plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP9). uPA and MMP9 actively participate in extracellular matrix reorganization and influence macrophages chemotaxis and cell migration. Although, TGF-β regulates uPA and MMP9 macrophages expression, the underlying intracellular signal mechanisms are not well elucidated so far. Here we have investigated the implication of TGF-β signaling in the regulation of uPA and MMP9 expression in RAW 264.7 macrophages. The expression of uPA and MMP9 was assessed by zymography, Western blotting and RT-PCR. The involvement of Smad, MAPK or NFκB signaling pathways was evaluated by using specific inhibitors. Our results indicated that TGF-β simultaneously increased uPA and reduced MMP9 expression. The Smad3, ERK1,2, and JNK1,2 signaling pathways seem to be the main mechanisms that mediate TGF-β-induced uPA expression. Whereas TGF-β-reduced MMP9 expression appears to be regulated independently by JNK1,2 activation and by NFκB signaling inhibition. Thus, our results suggested that, in murine macrophages, TGF-β differentially regulates uPA and MMP9 expressions through different intracellular signaling mechanisms. In addition, presented data may help in understanding the role of TGF-β in macrophages proteases regulation in inflammatory diseases.
authors.affiliation: Laboratory for Immunochemistry, Institute for Medical Research, University of Belgrade, Belgrade, Serbia.
authors.forename: Sonja S
authors.initials: SS
authors.lastname: Mojsilović
authors.forename: Juan F
authors.initials: JF
authors.lastname: Santibanez
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics* / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: macrophage; matrix metalloproteinase-9; signal transduction; transforming growth factor-beta; urokinase type plasminogen activator