Inhibition by antithrombin of cytokine-induced endothelial cell activation in vitro

Antithrombin (AT) is the physiological inhibitor of thrombin or other serine proteases of coagulation cascades. AT is also known to regulate inflammatory reactions. To determine whether AT inhibits cytokine-induced endothelial activation, we examined the effect of AT on an increase in endothelial cell adhesion molecules E-selectin and intercellular adhesion molecule-1 induced by tumor necrosis factor (TNF)-alpha. AT inhibited increase in E-selectin and intercellular adhesion molecule-1 expression induced by tumor necrosis factor-alpha. AT inhibited neither IkappaB degradation, nuclear translocation of NF-kappaB, nor nuclear binding activity of NF-kappaB. This suggests that AT did not inhibit the NF-kappaB pathway. AT inhibited physical interaction of p65 with p300, nuclear cofactor of NF-kappaB. Intracellular levels of cAMP increased by AT. These results suggest that AT inhibits endothelial cell activation by, at least in some part, inhibiting physical interaction of NF-kappaB with cAMP/p300 by increasing in intracellular levels of cAMP in endothelial cells. (C) 2003 Elsevier B.V. All rights reserved.