Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow.
ADAMTS13 cleaves ultralarge and hyperreactive von Willebrand factor (ULVWF) freshly released from activated endothelial cells to smaller and less active forms. This process may be affected by the amount of ULVWF released and the processing capacity of ADAMTS13, contributing to the development of thrombotic diseases. We examined the effects of inflammatory cytokines on the release and cleavage of ULVWF to evaluate potential links between inflammation and thrombosis. Human umbilical vein endothelial cells were treated with interleukin 6 (IL-6), IL-8, or tumor necrosis factor alpha (TNF-alpha), and the formation of platelet-decorated ULVWF strings was quantitated. IL-8 and TNF-alpha significantly stimulated the release of ULVWF in a dose-dependent manner. IL-6 induced ULVWF release only when it was in complex with the soluble IL-6 receptor. IL-6, but not IL-8 nor TNF-alpha, inhibited the cleavage of ULVWF strings by ADAMTS13 under flowing, but not static, conditions. These results suggest that inflammatory cytokines may stimulate the ULVWF release (IL-8 and TNF-alpha) and inhibit the ULVWF cleavage (IL-6), resulting in the accumulation of hyperreactive ULVWF in plasma and on the surface of endothelial cells to induce platelet aggregation and adhesion on the vascular endothelium. The findings describe a potential linkage between inflammation and thrombosis that may be of therapeutic importance.
Bernardo
Aubrey
A
Thrombosis Research Section, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Ball
Chalmette
C
Nolasco
Leticia
L
Moake
Joel F
JF
Dong
Jing-fei
JF
D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; D001464:Barium / Q000737:chemistry; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D016209:Interleukin-8 / Q000235:genetics / Q000494:pharmacology*; D007700:Kinetics; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000494:pharmacology; D020836:Protein Structure, Quaternary; D018123:Receptors, Interleukin / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D013268:Stimulation, Chemical; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology; D014508:Urea / Q000737:chemistry; D014841:von Willebrand Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000093242:Interleukin-6 Inhibitors
D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; D001464:Barium; D015850:Interleukin-6; D016209:Interleukin-8; D008666:Metalloendopeptidases; D011480:Protease Inhibitors; D018123:Receptors, Interleukin; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D014508:Urea; D014841:von Willebrand Factor; D000093242:Interleukin-6 Inhibitors; C099604:ADAMTS13 protein, human