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,
Departments of
*
Surgery,
Biochemistry, and
Human Biology, University of Maastricht, Maastricht, The Netherlands
Proinflammatory effects induced by the serine protease factor Xa
were investigated in HUVEC. Exposure of cells to factor Xa (5–80 nM)
concentration dependently stimulated the production of IL-6, IL-8, and
monocyte chemotactic protein-1 (MCP-1) and the expression of
E-selectin, ICAM-1, and VCAM-1, which was accompanied by
polymorphonuclear leukocyte adhesion. The effects of factor Xa were
blocked by antithrombin III, but not by the thrombin-specific inhibitor
hirudin, suggesting that factor Xa elicits these responses
directly and not via thrombin. IL-1
and TNF- were not implicated,
since neither the IL-1 receptor antagonist nor a TNF-neutralizing Ab
could suppress the factor Xa responses. Active site-inhibited factor Xa
and factor Xa depleted from 
-carboxyglutamic acid residues were
completely inactive. The effector cell protease receptor-1 (EPR-1)
seems not to be involved since anti-EPR-1 Abs failed to inhibit
cytokine production. Moreover, neither the factor X peptide
Leu83-Leu88, representing the inter-epidermal
growth factor sequence in factor Xa that mediates ligand binding
to EPR-1, nor the peptide AG1, corresponding to the EPR-1 sequence
Ser123-Pro137 implicated in factor Xa binding,
inhibited the factor Xa-induced cytokine production. In conclusion,
these findings indicate that factor Xa evokes a proinflammatory
response in endothelial cells, which requires both its catalytic and
-carboxyglutamic acid-containing domain. The receptor system
involved in these responses induced by factor Xa remains to be
established.
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