Skip to main content

Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Antithrombin prevents proinflammatory activation via NFκ and MAPK signaling pathways

Background

The serpin Antithrombin III (AT) is reported to have anticoagulatory as well as anti-inflammatory properties. AT inhibits cytokine secretion, leukocyte activation and neutrophil migration and it has been shown to be efficacious in treatment of septic disorders.

The molecular mechanism underlying the anti-inflammatory effects of AT III is still unclear. We investigated the influence of AT on NFκB- and MAPK-signaling, both well known proinflammatory signaling pathways in endothelial cells (EC) and monocytes (MO).

Methods

EC or MO were incubated with TNF-α (40 ng/ml) or LPS (10 μg/ml), respectively, in presence or absence of AT (0–30 IU/ml). Activation of the transcription factors NFκB and AP-1 (EMSA), the phosphorylation and degradation of the NFκB inhibitory protein IκBα, JNK/SAPK activation (Western Blot), as well as NFκB regulated protein- and gene expression (Tissue Factor [TF], TNF-α, IL-6) (ELISA, rtPCR) were analysed under influence of AT III, AT III isoforms and binding-modified AT.

Results

AT inhibited activation of NFκB in a dose-dependent manner by preventing phosphorylation and degradation of the inhibitor protein IκBα. AT prevented the activation of the p54 subunit of JNK/SAPK. TF and cytokine production were markedly reduced by AT III (20% of control). The b-isoform of AT, reported to have a higher affinity for glycosaminoglycans (GAGs), was more effective in preventing this proinflammatory activation than the ATα isoform. AT without heparin-binding site had no effect.

Conclusion

AT prevents NFκB- and MAPK-activation in EC and MO when given in therapeutical doses. The anti-inflammatory properties of AT III seem to depend on the interaction of the heparin-binding site of AT with GAGs on cell surface.

Author information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Oelschläger, C., Staubitz, A., Römsich, J. et al. Antithrombin prevents proinflammatory activation via NFκ and MAPK signaling pathways. Crit Care 6, P115 (2002). https://doi.org/10.1186/cc1569

Download citation

Keywords

  • Endothelial Cell
  • Glycosaminoglycan
  • Antithrombin
  • MAPK Signaling
  • MAPK Signaling Pathway