Submitted March 7, 2008
Accepted August 11, 2008
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, Chih-Yuan Ma, Cheng-Hsiang Kuo, Bi-Ing Chang, Chuan-Fa Chang, Chun-Hung Lin, Chi-Huey Wong, and Hua-Lin Wu*
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan
Genomics Research Center, Academia Sinica, Taipei, Taiwan
Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
* Corresponding author; email: halnwu{at}mail.ncku.edu.tw.
Thrombomodulin (TM), a widely expressing glycoprotein and originally identified in vascular endothelium, is an important cofactor in the protein C anti-coagulant system. TM appears to exhibit anti-inflammatory ability through both protein C dependent and independent pathways. We presently have demonstrated that recombinant N-terminal lectin-like 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-
B 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.
