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.
1. Medizinische Klinik and Deutsches Herzzentrum, Technische Universität München, Klinikum rechts der Isar, Lazarettstr. 36, D-80636 München, Germany. gawaz@dhm.mhn.de
Meinrad
M
Gawaz
Sharon
S
Page
Steffen
S
Massberg
Caroline
C
Nothdurfter
Marion
M
Weber
Claudia
C
Fisher
Martin
M
Ungerer
Korbinian
K
Brand
D001792:Blood Platelets / Q000502:physiology*; D002450:Cell Communication; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051550:I-kappa B Kinase; D007375:Interleukin-1 / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D015539:Platelet Activation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology
D018932:Chemokine CCL2; D007375:Interleukin-1; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human