A key role for Toll-like receptor-3 in disrupting the hemostasis balance on endothelial cells.
Various virus infections cause dysfunctional hemostasis and in some instances lead to the development of viral hemorrhagic fever syndrome. How do diverse viruses induce the expression of tissue factor on vascular cells? We hypothesize that a direct stimulation of pattern recognition receptors (PRR) by viral nucleic acids may be the key. Double-stranded RNA (dsRNA) is produced by many viruses and is recognized by various PRR, including Toll-like receptor-3 (TLR3). We have investigated whether poly I:C, a model for viral dsRNA, can influence cellular hemostasis. Poly I:C could up-regulate tissue factor and down-regulate thrombomodulin expression on endothelial cells but not on monocytes. The response to poly I:C was diminished upon small interfering RNA (siRNA)-mediated inhibition of TLR3, but not other PRR. In vivo, application of poly I:C induced similar changes in the aortic endothelium of mice as determined by enface microscopy. D-dimer, a circulating marker for enhanced coagulation and fibrinolysis, and tissue fibrin deposition was elevated. All the hemostasis-related responses to poly I:C, but not cytokine secretion, were blunted in TLR3(-/-) mice. Hence, the activation of TLR3 can induce the procoagulant state in the endothelium, and this could be relevant for understanding the mechanisms of viral stimulation of hemostasis.
Shibamiya
Aya
A
Institute for Biochemistry, Justus-Liebig-University, Giessen, Germany.
Hersemeyer
Karin
K
Schmidt Wöll
Thomas
T
Sedding
Daniel
D
Daniel
Jan-Marcus
JM
Bauer
Stefan
S
Koyama
Takatoshi
T
Preissner
Klaus T
KT
Kanse
Sandip M
SM
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects; D006487:Hemostasis / Q000502:physiology*; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008856:Microscopy, Fluorescence; D011070:Poly I-C / Q000494:pharmacology; D034741:RNA, Small Interfering; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018180:Thrombomodulin / Q000187:drug effects / Q000378:metabolism; D013925:Thromboplastin / Q000187:drug effects / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D007369:Interferon Inducers; D034741:RNA, Small Interfering; D051192:Receptors, Pattern Recognition; C519703:TLR3 protein, mouse; D018180:Thrombomodulin; D051196:Toll-Like Receptor 3; D013925:Thromboplastin; D011070:Poly I-C