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Antithrombin prevents proinflammatory activation via NFκ and MAPK signaling pathways
Critical Care volume 6, Article number: P115 (2002)
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).
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.
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.
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.
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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
- Endothelial Cell
- MAPK Signaling
- MAPK Signaling Pathway