Transient platelet interaction induces MCP-1 production by endothelial cells via I kappa B kinase complex activation.

Activated platelets alter endothelial chemotactic and adhesive properties. Transient interaction of alpha-thrombin-activated platelets with endothelial cells is sufficient to induce secretion of the NF-kappa B-regulated chemokine MCP-1. To evaluate upstream signaling events in platelet-induced NF-kappa B activation, we compared the effect of platelets, IL-1 beta or TNF-alpha on I kappa B kinase (IKK) complex activation and I kappa B 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-1 beta, whereas TNF-alpha elicited a rapid induction of IKK. Differential effects were also found on I kappa B-alpha/epsilon degradation, while IKK levels were unaffected. Furthermore, overexpression of kinase-inactive IKK-beta KA, as well as NIKKA, inhibited platelet- or IL-1 beta-induced kappa B-, MCP-1- or VCAM-1-dependent transcription. Using adeno-associated virus particles for cell transduction, we found that IKK-beta 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.