Lectin-like domain of thrombomodulin binds to its specific ligand Lewis Y antigen and neutralizes lipopolysaccharide-induced inflammatory response.
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-kappaB 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.
Shi
Chung-Sheng
CS
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Taiwan.
Shi
Guey-Yueh
GY
Hsiao
Hsi-Min
HM
Hsiao
Shi-Ming
SM
Kao
Yuan-Chung
YC
Kuo
Kuan-Lin
KL
Ma
Chih-Yuan
CY
Kuo
Cheng-Hsiang
CH
Chang
Bi-Ing
BI
Chang
Chuan-Fa
CF
Lin
Chun-Hung
CH
Wong
Chi-Huey
CH
Wu
Hua-Lin
HL
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000517:prevention & control; D007711:Klebsiella pneumoniae / Q000378:metabolism / Q000472:pathogenicity; D007983:Lewis Blood Group Antigens / Q000378:metabolism*; D008024:Ligands; D008070:Lipopolysaccharides / Q000378:metabolism / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018805:Sepsis / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects; D018180:Thrombomodulin / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism*
D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen; D008024:Ligands; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011994:Recombinant Proteins; D018180:Thrombomodulin