Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide.
J Clin Invest
; 105(4): 497-504, 2000 Feb.
Article
en En
| MEDLINE
| ID: mdl-10683379
ABSTRACT
Lipopolysaccharide (LPS) is the main inducer of shock and death in Gram-negative sepsis. Recent evidence suggests that LPS-induced signal transduction begins with CD14-mediated activation of 1 or more Toll-like receptors (TLRs). The lipid A analogues lipid IVa and Rhodobacter sphaeroides lipid A (RSLA) exhibit an uncommon species-specific pharmacology. Both compounds inhibit the effects of LPS in human cells but display LPS-mimetic activity in hamster cells. We transfected human TLR4 or human TLR2 into hamster fibroblasts to determine if either of these LPS signal transducers is responsible for the species-specific pharmacology. RSLA and lipid IVa strongly induced NF-kappaB activity and IL-6 release in Chinese hamster ovary fibroblasts expressing CD14 (CHO/CD14), but these compounds antagonized LPS antagonists in CHO/CD14 fibroblasts that overexpressed human TLR4. No such antagonism occurred in cells overexpressing human TLR2. We cloned TLR4 from hamster macrophages and found that human THP-1 cells expressing the hamster TLR4 responded to lipid IVa as an LPS mimetic, as if they were hamster in origin. Hence, cells heterologously overexpressing TLR4 from different species acquired a pharmacological phenotype with respect to recognition of lipid A substructures that corresponded to the species from which the TLR4 transgene originated. These data suggest that TLR4 is the central lipid A-recognition protein in the LPS receptor complex.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Glicoproteínas de Membrana
/
Lipopolisacáridos
/
Receptores de Superficie Celular
/
Receptores de Lipopolisacáridos
/
Proteínas de Drosophila
Idioma:
En
Revista:
J Clin Invest
Año:
2000
Tipo del documento:
Article