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Lectin-like domain of thrombomodulin binds to its specific ligand Lewis Y antigen and neutralizes lipopolysaccharide-induced inflammatory response
- 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.
- Subjects :
- Lipopolysaccharides
Male
Gram-negative bacteria
Lipopolysaccharide
MAP Kinase Signaling System
Thrombomodulin
CD14
Immunology
Inflammation
Biology
Ligands
Biochemistry
Cell Line
Microbiology
Mice
chemistry.chemical_compound
Lewis Blood Group Antigens
Antigen
Sepsis
medicine
Animals
Humans
Protein kinase A
Immunobiology
Binding Sites
Macrophages
NF-kappa B
Cell Biology
Hematology
biology.organism_classification
Recombinant Proteins
Protein Structure, Tertiary
Klebsiella pneumoniae
chemistry
medicine.symptom
Gram-Negative Bacterial Infections
Protein C
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 15280020 and 00064971
- Volume :
- 112
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....ef767e4f02b28384887832db632687a5