Regulation of monocyte/macrophage function by factor VII activating protease (FSAP).
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.
Internal Medicine I/Cardiology and Angiology, Innere Medizin I - Kardiologie, Bad Homburg, Germany. Electronic address: mariana.parahuleva@innere.med.uni-giessen.de.
Mariana S
MS
Parahuleva
Robert
R
Maj
Hans
H
Hölschermann
Behnoush
B
Parviz
Yaser
Y
Abdallah
Ali
A
Erdogan
Harald
H
Tillmanns
Sandip M
SM
Kanse
D050197:Atherosclerosis / Q000473:pathology; D002318:Cardiovascular Diseases / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
D020672:I-kappa B Proteins; D016328:NF-kappa B; C433550:HABP2 protein, human; D012697:Serine Endopeptidases
Atherosclerosis; FSAP; Monocytes/macrophages; NF-κB; Vascular inflammation