The Journal of Experimental Medicine
Janeway's Immunobiology 7th Edition
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Published 2 September 2002. doi:10.1084/jem.20020077
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© Rockefeller University Press, 0022-1007/2002/9/565/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 5, September 2, 2002 565-577
The Lectin-like Domain of Thrombomodulin Confers Protection from Neutrophil-mediated Tissue Damage by Suppressing Adhesion Molecule Expression via Nuclear Factor {kappa}B and Mitogen-activated Protein Kinase Pathways

Edward M. Conway1, Marlies Van de Wouwer1, Saskia Pollefeyt1, Kerstin Jurk2, Hugo Van Aken2, Astrid De Vriese1, Jeffrey I. Weitz3, Hartmut Weiler4, Peter W. Hellings1, Paul Schaeffer5, Jean-Marc Herbert5, Désiré Collen1 and Gregor Theilmeier2

1 The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, B-3000 Leuven, Belgium
2 Klinik und Poliklinik für Anästhesiologie und Operative Intensivmedizin, University of Muenster, D-48149 Muenster, Germany
3 McMaster University and Hamilton Civic Hospital Research Center, Hamilton L8V-1C3, Canada
4 The Blood Center for Southeastern Wisconsin, Milwaukee, WI 53233
5 Sanofi-Synthelabo, Thrombosis Research Department, 31036 Toulouse, France

Address correspondence to Edward M. Conway, Center for Transgene Technology and Gene Therapy, KU Leuven, Gasthuisberg O&N, 9th Floor, Herestraat 49, B-3000 Leuven, Belgium. Phone: +32-16-345780; Fax: +32-16-345990; E-mail: ed.conway{at}med.kuleuven.ac.be

Thrombomodulin (TM) is a vascular endothelial cell (EC) receptor that is a cofactor for thrombin-mediated activation of the anticoagulant protein C. The extracellular NH2-terminal domain of TM has homology to C-type lectins that are involved in immune regulation. Using transgenic mice that lack this structure (TMLeD/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. TMLeD/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 {kappa}B and activation of ERK1/2, 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.

Key Words: inflammation • coagulation • endotoxin • sepsis • protein C


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