Regulation of monocyte/macrophage function by factor VII activating protease (FSAP).

ABSTRACT

OBJECTIVE: Factor VII activating protease (FSAP) is a novel regulator of vascular inflammation and hemostasis. However, the molecular mechanism by which circulating FSAP influences inflammatory events and progression of atherosclerosis is not yet entirely understood. Here we have investigated the influence of FSAP on monocyte/macrophage functions. METHODS: We stimulated human monocyte-derived macrophages with FSAP and analyzed their cellular responses. RESULTS: FSAP induced IκB-dependent NF-κB activation in a time- and concentration-dependent fashion. FSAP also activated the phosphorylation and proteolytic degradation of the inhibitor protein IκBα. The phosphorylation of the p65 subunit of NF-κB was induced by FSAP, which is known to contribute to the enhancement of DNA-binding activity of NF-κB. Concomitantly, FSAP up-regulated the expression of pro-inflammatory cytokines, matrix metalloproteinases, cell adhesion molecules and tissue factor. In the presence of FSAP there was increased monocytes adhesion and transendothelial migration in a beta2 integrin dependent manner. CONCLUSIONS: Our findings suggest that FSAP activates the NF-κB pathway and the associated downstream pro-inflammatory factors in monocytic cells. This adds to a spectrum of FSAP effects on the vascular system that may explain its association with cardiovascular diseases.