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Min Guo, Sanjeev K. Sahni, Abha Sahni, Charles W. Francis
Fibrinogen regulates the expression of inflammatory chemokines through NF-B activation of endothelial cells
The objective of this study was to characterize the role of fibrinogen in stimulating expression of inflammatory chemokines in endothelial cells through NF-B activation. Human umbilical vein endothelial cells (HUVEC) were exposed to fibrinogen up to 3,000 g/ml, and NF-B activation was assessed using electrophoretic mobility shift assay (EMSA). Fibrinogen exposure resulted in a concentration dependent increase in NF-B activation that reached a maximum at 1,000 g/ml after 4 hours and was sustained up to 24 hours. The effect was inhibited by antibodies to v3 and 51 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-B. 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 IB kinase inhibitor, prevented up-regulation of MCP-1 by fibrinogen, linking this response to NF-B activation. From our findings, we conclude that fibrinogen regulates NF-B activation and expression of inflammatory chemokines in endothelial cells and may be involved in mediating inflammatory processes.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 92, 10/2004
Pages: 858 - 866