The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappaB and mitogen-activated protein kinase pathways.
Thrombomodulin (TM) is a vascular endothelial cell (EC) receptor that is a cofactor for thrombin-mediated activation of the anticoagulant protein C. The extracellular NH(2)-terminal domain of TM has homology to C-type lectins that are involved in immune regulation. Using transgenic mice that lack this structure (TM(LeD/LeD)), we show that the lectin-like domain of TM interferes with polymorphonuclear leukocyte (PMN) adhesion to ECs by intercellular adhesion molecule 1-dependent and -independent pathways through the suppression of extracellular signal-regulated kinase (ERK)(1/2) activation. TM(LeD/LeD) mice have reduced survival after endotoxin exposure, accumulate more PMNs in their lungs, and develop larger infarcts after myocardial ischemia/reperfusion. The recombinant lectin-like domain of TM suppresses PMN adhesion to ECs, diminishes cytokine-induced increase in nuclear factor kappaB and activation of ERK(1/2), and rescues ECs from serum starvation, findings that may explain why plasma levels of soluble TM are inversely correlated with cardiovascular disease. These data suggest that TM has antiinflammatory properties in addition to its role in coagulation and fibrinolysis.
The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, B-3000 Leuven, Belgium. ed.conway@med.kuleuven.ac.be
Edward M
EM
Conway
Marlies
M
Van de Wouwer
Saskia
S
Pollefeyt
Kerstin
K
Jurk
Hugo
H
Van Aken
Astrid
A
De Vriese
Jeffrey I
JI
Weitz
Hartmut
H
Weiler
Peter W
PW
Hellings
Paul
P
Schaeffer
Jean-Marc
JM
Herbert
Désiré
D
Collen
Gregor
G
Theilmeier
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002448:Cell Adhesion; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D005260:Female; D007249:Inflammation / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D037102:Lectins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology*; D017434:Protein Structure, Tertiary; D018180:Thrombomodulin / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*
D037102:Lectins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018180:Thrombomodulin; D018799:Intercellular Adhesion Molecule-1; D020928:Mitogen-Activated Protein Kinases