Antithrombin III inhibits nuclear factor kappaB activation in human monocytes and vascular endothelial cells.
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 kappaB (NF-kappaB), a transcription factor involved in immediate early gene activation during inflammation. AT III inhibited agonist-induced DNA binding of NF-kappaB in cultured human monocytes and endothelial cells in a dose-dependent manner, suggesting that AT III interferes with signal transduction leading to NF-kappaB activation. This idea was supported by demonstrating that AT III prevents the phosphorylation and proteolytic degradation of the inhibitor protein IkappaBalpha. In parallel to reducing NF-kappaB activity, AT III inhibited the expression of interleukin-6, tumor necrosis factor-alpha, and tissue factor, genes known to be under the control of NF-kappaB. The observation that chemically modified AT III that lacks heparin-binding capacity had no effect on NF-kappaB 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 beta-isoform, known to have higher affinity for glycosaminoglycans, is more effective in preventing NF-kappaB transactivation than alpha-AT III. These data indicate that AT III can alter inflammatory processes via inhibition of NF-kappaB activation.
Oelschläger
Christian
C
Division of Cardiology, Department of Internal Medicine, University of Giessen, Germany.
Römisch
Jürgen
J
Staubitz
Anne
A
Stauss
Harald
H
Leithäuser
Boris
B
Tillmanns
Harald
H
Hölschermann
Hans
H
D000990:Antithrombin III / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D002470:Cell Survival; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D006493:Heparin / Q000378:metabolism; D006801:Humans; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D020033:Protein Isoforms / Q000494:pharmacology; D018805:Sepsis / Q000188:drug therapy; D014471:Umbilical Veins
D016328:NF-kappa B; D020033:Protein Isoforms; D000990:Antithrombin III; D006493:Heparin