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

Chung Sheng Shi, Guey Yueh Shi, Shi Ming Hsiao, Yuan Chung Kao, Kuan Lin Kuo, Ma Chih-Yuan, Cheng Hsiang Kuo, Bi Ing Chang, Chuan Fa Chang, Chun Hung Lin, Chi Huey Wong, Hua Lin Wu

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121 Citations (Scopus)

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 Gramnegative 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 mitogenactivated 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 Gramnegative bacterial infections.

Original languageEnglish
Pages (from-to)3661-3670
Number of pages10
JournalBlood
Volume112
Issue number9
DOIs
Publication statusPublished - 2008 Nov 1

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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