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Blood, 1 June 2002, Vol. 99, No. 11, pp. 4015-4020
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Antithrombin III inhibits nuclear factor  B activation in human
monocytes and vascular endothelial cells
Christian Oelschläger,
Jürgen Römisch,
Anne Staubitz,
Harald Stauss,
Boris Leithäuser,
Harald Tillmanns, and
Hans Hölschermann
From the Division of Cardiology, Department of Internal
Medicine, University of Giessen, Germany; and Aventis Behring GmbH,
Research, Marburg, Germany.
The serpin antithrombin III (AT III), the most important natural
inhibitor of thrombin activity, has been shown to exert marked anti-inflammatory properties and proven to be efficacious in
experimental models of sepsis, septic shock, and disseminated
intravascular coagulation. Moreover, clinical observations suggest a
possible therapeutic role for AT III in septic disorders. The molecular mechanism, however, by which AT III attenuates inflammatory events is
not yet entirely understood. We show here that AT III potently blocks
the activation of nuclear factor  B (NF-B), a transcription factor
involved in immediate early gene activation during inflammation. AT III
inhibited agonist-induced DNA binding of NF-B in cultured human
monocytes and endothelial cells in a dose-dependent manner, suggesting that AT III interferes with signal transduction leading to
NF-B activation. This idea was supported by demonstrating that
AT III prevents the phosphorylation and proteolytic degradation of the
inhibitor protein IB . In parallel to reducing NF-B activity, AT III inhibited the expression of interleukin-6, tumor necrosis factor-, and tissue factor, genes known to be under the control of
NF-B. The observation that chemically modified AT III that lacks heparin-binding capacity had no effect on NF-B activation supports the current understanding that the inhibitory potency of AT
III depends on the interaction of AT III with heparinlike cell surface
glycosaminoglycans. This hypothesis was underscored by the finding that
the AT III  -isoform, known to have higher affinity for
glycosaminoglycans, is more effective in preventing NF-B
transactivation than -AT III. These data indicate that AT III can
alter inflammatory processes via inhibition of NF-B activation.
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