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Lectin-like domain of thrombomodulin binds to its specific ligand Lewis Y antigen and neutralizes lipopolysaccharide-induced inflammatory response

Authors :
Chung-Sheng, Shi
Guey-Yueh, Shi
Hsi-Min, Hsiao
Shi-Ming, Hsiao
Yuan-Chung, Kao
Kuan-Lin, Kuo
Chih-Yuan, Ma
Cheng-Hsiang, Kuo
Bi-Ing, Chang
Chuan-Fa, Chang
Chun-Hung, Lin
Chi-Huey, Wong
Hua-Lin, Wu
Source :
Blood. 112:3661-3670
Publication Year :
2008
Publisher :
American Society of Hematology, 2008.

Abstract

Thrombomodulin (TM), a widely expressing glycoprotein originally identified in vascular endothelium, is an important cofactor in the protein C anticoagulant system. TM appears to exhibit anti-inflammatory ability through both protein C–dependent and –independent pathways. We presently have demonstrated that recombinant N-terminal lectinlike domain of TM (rTMD1) functions as a protective agent against sepsis caused by Gram-negative bacterial infections. rTMD1 caused agglutination of Escherichia coli and Klebsiella pneumoniae and enhanced the macrophage phagocytosis of these Gram-negative bacteria. Moreover, rTMD1 bound to the Klebsiella pneumoniae and lipopolysaccharide (LPS) by specifically interacting with Lewis Y antigen. rTMD1 inhibited LPS-induced inflammatory mediator production via interference with CD14 and LPS binding. Furthermore, rTMD1 modulated LPS-induced mitogen-activated protein kinase and nuclear factor-κB signaling pathway activations and inducible nitric oxide synthase expression in macrophages. Administration of rTMD1 protected the host by suppressing inflammatory responses induced by LPS and Gram-negative bacteria, and enhanced LPS and bacterial clearance in sepsis. Thus, rTMD1 can be used to defend against bacterial infection and inhibit LPS-induced inflammatory responses, suggesting that rTMD1 may be valuable in the treatment of severe inflammation in sepsis, especially in Gram-negative bacterial infections.

Details

ISSN :
15280020 and 00064971
Volume :
112
Database :
OpenAIRE
Journal :
Blood
Accession number :
edsair.doi.dedup.....ef767e4f02b28384887832db632687a5