Transient Platelet Interaction Induces MCP-1 Production by Endothelial Cells via IκB Kinase Complex Activation

Summary

Activated platelets alter endothelial chemotactic and adhesive properties. Transient interaction of α-thrombin-activated platelets with endothelial cells is sufficient to induce secretion of the NF-κBregulated chemokine MCP-1. To evaluate upstream signaling events in platelet-induced NF-κB activation, we compared the effect of platelets, IL-1β or TNF-α on IκB kinase (IKK) complex activation and IκB phosphorylation/proteolysis. Kinase assays demonstrated that platelets induced a slow increase in IKK activity over 30 min, which was similar, but not identical, to IL-1β, whereas TNF-α elicited a rapid induction of IKK. Differential effects were also found on IκB-α/ε degradation, while IKK levels were unaffected. Furthermore, overexpression of kinase-inactive IKK-β_KA, as well as NIK_KA, inhibited plateletor IL-1β-induced κB-, MCP-1or VCAM-1-dependent transcription. Using adeno-associated virus particles for cell transduction, we found that IKK-β_KA substantially reduced stimulus-induced MCP-1 secretion. Platelet-induced signaling and resulting endothelial gene expression may play a role in early atherogenesis as well as plaque progression/destabilization.

Meinrad Gawaz, Sharon Page, and Steffen Massberg contributed equally to this work.

Keywords

Platelets - endothelium - NF-κB - IKK complex - adenoassociated virus

• References

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