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

CS Shi, GY Shi, HM Hsiao, YC Kao… - Blood, The Journal …, 2008 - ashpublications.org
CS Shi, GY Shi, HM Hsiao, YC Kao, KL Kuo, CY Ma, CH Kuo, BI Chang, CF Chang, CH Lin
Blood, The Journal of the American Society of Hematology, 2008ashpublications.org
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 …
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.
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