GM‐CSF activates RhoA, integrin and MMP expression in human monocytic cells

Abstract

Monocyte migration is one of the key events occurring in the early stage of atherosclerosis. This process includes monocytic adhesion to and penetration through the arterial intima. In such an environment, many factors stimulate the monocytes to enhance integrin activation and extracellular matrix degradation. To investigate the coordinative operation of these two events in relation to monocyte migration, we paid particular attention to the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on monocytes in terms of RhoA activation and matrix metalloproteinase (MMP) expression. RhoA and integrin clustering were activated by GM-CSF, monocyte chemoattractant protein-1 (MCP-1) and platelet-derived growth factor-BB (PDGF-BB) in human monocytic cell lines. Furthermore, enhancement of migration was observed with stimulation by MCP-1 and PDGF-BB. Granulocyte-macrophage colony-stimulating factor did not enhance the migration, even though it activated RhoA and integrin. However, GM-CSF is known to stimulate monocytes to express MCP-1, suggesting the presence of an indirect mechanism for GM-CSF-mediated migratory activity. In contrast, only GM-CSF enhanced the expression of MMP-1 and MMP-9. These results provide evidence that GM-CSF has multiple functions enhancing monocytic migration via RhoA and integrin activation, and via MMP expression.

Granulocyte-Macrophage Colony-Stimulating Factor- and Tumor Necrosis Factor Alpha-Mediated Matrix Metalloproteinase Production by Human Osteoblasts and Monocytes after Infection withBrucella abortus

“…In the present study an increased MMP-2 activity was detected in supernatants from B. abortus-infected osteoblasts. Previous studies have shown that in several cell lines MMP production can be stimulated by GM-CSF (25,26). Since this factor is produced by Brucella-infected osteoblasts, as shown here and also in our previous study (11), we assessed whether osteoblast-derived GM-CSF may induce MMP-2 in these same cells.…”

“…Proinflammatory cytokines and growth factors have been shown to stimulate MMPs secretion by different cellular types (20,25,26,43), in some instances in an autocrine fashion (2,21). To test whether MMP-2 induction in Brucella-infected osteoblasts may be mediated by cytokines or growth factors produced by these same cells, the levels of IL-1␤, IL-6, TNF-␣, and GM-CSF were measured in culture supernatants.…”

“…GM-CSF has been shown to stimulate MMP-9 production by monocytes (25,54). In addition, we have shown here (Fig.…”

Potential Role of Fibroblast-Like Synoviocytes in Joint Damage Induced by Brucella abortus Infection through Production and Induction of Matrix Metalloproteinases

“…In contrast, MMP-9 secretion was not stimulated by supernatants from noninfected FLS. Several cytokines and growth factors have been shown to stimulate MMP-9 production by monocytes, including IL-1␤, TNF-␣, and GM-CSF, and were candidates for mediators of the stimulating effect of synoviocyte culture supernatants (19,26,57). However, we have mentioned above that Brucella-infected FLS did not secrete IL-1␤ or TNF-␣.…”

“…Since GM-CSF and IL-6 are also known to induce MMP production by different cell types (8,26,46) and both factors are produced by Brucella-infected FLS ( Fig. 2A and B), we decided to test their potential role as mediators of the MMP-9 induction by culture supernatants from infected FLS.…”