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Fibrinogen regulates the expression of inflammatory chemokines through NF-κB activation of endothelial cells

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
Topic:

Paediatric Haemostasis

DOI: http://dx.doi.org/10.1160/TH04-04-0261
Issue: 2004: 92/4 (Oct) pp. 672-895
Pages: 858-866

Fibrinogen regulates the expression of inflammatory chemokines through NF-κB activation of endothelial cells

Min Guo, Sanjeev K. Sahni, Abha Sahni, Charles W. Francis
Hematology-Oncology Unit, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA

Summary

The objective of this study was to characterize the role of fibrinogen in stimulating expression of inflammatory chemokines in endothelial cells through NF-κB activation. Human umbilical vein endothelial cells (HUVEC) were exposed to fibrinogen up to 3,000 µg/ml, and NF-κB activation was assessed using electrophoretic mobility shift assay (EMSA). Fibrinogen exposure resulted in a concentration dependent increase in NF-κB activation that reached a maximum at 1,000 µg/ml after 4 hours and was sustained up to 24 hours. The effect was inhibited by antibodies to αvβ3 and α5β1 and by the GRGDS peptide, indicating integrin involvement. Preincubation with Mn2+ lowered the fibrinogen concentration-dependence, consistent with integrin activation. Supershift assays demonstrated involvement of the p50, p65 and c-Rel components of NF-κB. Fibrinogen exposure also resulted in up-regulation of expression of monocyte chemoattractant protein-1 (MCP-1) and of interleukin-8 as shown by RNase protection assays and by real-time RT-PCR. Increased secretion of MCP-1 was confirmed by ELISA. Parthenolide, an IκB kinase inhibitor, prevented up-regulation of MCP-1 by fibrinogen, linking this response to NF-κB activation. From our findings, we conclude that fibrinogen regulates NF-κB activation and expression of inflammatory chemokines in endothelial cells and may be involved in mediating inflammatory processes.