Matrix metalloproteinase inhibitors prevent the release and proteolytic activity of monocyte/macrophage-derived microparticles.

Abstract

The role of monocyte/macrophage-derived microparticles (MPs) in the pathophysiology of cancer and chronic inflammatory diseases has been reported; nevertheless, the mechanism underlying microparticles release is currently unclear. The aim of the current study was to investigate whether matrix metalloproteinase (MMP) inhibitors could prevent MP shedding from stimulated human monocyte/macrophage. Microparticles were obtained by isolated peripheral blood mononuclear cells after stimulation with the calcium ionophore, A23187. MP shedding, intracellular calcium concentration, analysis of RhoA expression, and proteolytic activities of isolated MPs were assessed in the absence or presence of MMP inhibitors. We demonstrated that MMP inhibitors remarkably prevented MP shedding in a concentration-dependent manner with IC50 values in the nano- to micromolar range. Such an effect was related to their ability to reduce the intracellular Ca2+ levels induced by the calcium ionophore and the consequent translocation of RhoA from cytosol to membrane. Furthermore, MMP inhibitors could inhibit the proteolytic activity of cell-derived MPs. The current study provide evidence that MMP inhibitors can prevent MPs shedding from stimulated human monocyte/macrophage and the proteolytic activity of released MPs. Finally, the most active compound tested might represent the lead compound of a new class of molecules with therapeutic potential in cancer and chronic inflammatory diseases.