Protection from lethal gram-negative bacterial sepsis by targeting Toll-like receptor 4.
Details
Serval ID
serval:BIB_7916D743A3A0
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Protection from lethal gram-negative bacterial sepsis by targeting Toll-like receptor 4.
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN
1091-6490
Publication state
Published
Issued date
02/2009
Peer-reviewed
Oui
Volume
106
Number
7
Pages
2348-2352
Language
english
Abstract
Toll-like receptor 4 (TLR4), the signal-transducing molecule of the LPS receptor complex, plays a fundamental role in the sensing of LPS from gram-negative bacteria. Activation of TLR4 signaling pathways by LPS is a critical upstream event in the pathogenesis of gram-negative sepsis, making TLR4 an attractive target for novel antisepsis therapy. To validate the concept of TLR4-targeted treatment strategies in gram-negative sepsis, we first showed that TLR4(-/-) and myeloid differentiation primary response gene 88 (MyD88)(-/-) mice were fully resistant to Escherichia coli-induced septic shock, whereas TLR2(-/-) and wild-type mice rapidly died of fulminant sepsis. Neutralizing anti-TLR4 antibodies were then generated using a soluble chimeric fusion protein composed of the N-terminal domain of mouse TLR4 (amino acids 1-334) and the Fc portion of human IgG1. Anti-TLR4 antibodies inhibited intracellular signaling, markedly reduced cytokine production, and protected mice from lethal endotoxic shock and E. coli sepsis when administered in a prophylactic and therapeutic manner up to 13 h after the onset of bacterial sepsis. These experimental data provide strong support for the concept of TLR4-targeted therapy for gram-negative sepsis.
Keywords
endotoxic shock, Gram-negative bacteria, lipopolysaccharide, TLR4
Pubmed
Web of science
Open Access
Yes
Create date
12/02/2009 15:46
Last modification date
20/08/2019 15:35