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 (TGF-) 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- 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- 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 NFB signaling pathways was evaluated by using specific inhibitors. Our results indicated that TGF- 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--induced uPA expression. Whereas TGF--reduced MMP9 expression appears to be regulated independently by JNK1,2 activation and by NFB signaling inhibition. Thus, our results suggested that, in murine macrophages, TGF- differentially regulates uPA and MMP9 expressions through different intracellular signaling mechanisms. In addition, presented data may help in understanding the role of TGF- in macrophages proteases regulation in inflammatory diseases.