Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide

Lien, Egil; Means, Terry K.; Heine, Holger; Yoshimura, Atsutoshi; Kusumoto, Shoichi; Fukase, Koichi; Fenton, Matthew J.; Oikawa, Masato; Qureshi, Nilofer; Monks, Brian G.; Finberg, Robert W.; Ingalls, Robin R.; Golenbock, Douglas T.

doi:10.1172/jci8541

Cited by 691 publications

(511 citation statements)

References 42 publications

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“…TLR4 is involved in this ligand-specific recognition of LPS (17,18). Recently, the involvement of MD-2 in this ligand-specific recognition of LPS was also demonstrated (19).…”

Section: Identification Of Mouse Md-2 Residues Important Formentioning

confidence: 93%

Identification of Mouse MD-2 Residues Important for Forming the Cell Surface TLR4-MD-2 Complex Recognized by Anti-TLR4-MD-2 Antibodies, and for Conferring LPS and Taxol Responsiveness on Mouse TLR4 by Alanine-Scanning Mutagenesis

Kawasaki

Nogawa

Nishijima

2003

The Journal of Immunology

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The expression of MD-2, which associates with Toll-like receptor (TLR) 4 on the cell surface, confers LPS and LPS-mimetic Taxol responsiveness on TLR4. Alanine-scanning mutagenesis was performed to identify the mouse MD-2 residues important for conferring LPS and Taxol responsiveness on mouse TLR4, and for forming the cell surface TLR4-MD-2 complex recognized by anti-TLR4-MD-2 Ab MTS510. Single alanine mutations were introduced into mouse MD-2 (residues 17–160), and the mutants were expressed in a human cell line expressing mouse TLR4. Mouse MD-2 mutants, in which a single alanine mutation was introduced at Cys37, Leu71, Leu78, Cys95, Tyr102, Cys105, Glu111, Val113, Ile117, Pro118, Phe119, Glu136, Ile138, Leu146, Cys148, or Thr152, showed dramatically reduced ability to form the cell surface mouse TLR4-mouse MD-2 complex recognized by MTS510, and the mutants also showed reduced ability to confer LPS and Taxol responsiveness. In contrast, mouse MD-2 mutants, in which a single alanine mutation was introduced at Tyr34, Tyr36, Gly59, Val82, Ile85, Phe126, Pro127, Gly129, Ile153, Ile154, and His155 showed normal ability to form the cell surface mouse TLR4-mouse MD-2 complex recognized by MTS510, but their ability to confer LPS and Taxol responsiveness was apparently reduced. These results suggest that the ability of MD-2 to form the cell surface mouse TLR4-mouse MD-2 complex recognized by MTS510 is essential for conferring LPS and Taxol responsiveness on TLR4, but not sufficient. In addition, the required residues at codon numbers 34, 85, 101, 122, and 153 for the ability of mouse MD-2 to confer LPS responsiveness are partly different from those for Taxol responsiveness.

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“…TLR4 is involved in this ligand-specific recognition of LPS (17,18). Recently, the involvement of MD-2 in this ligand-specific recognition of LPS was also demonstrated (19).…”

Section: Identification Of Mouse Md-2 Residues Important Formentioning

confidence: 93%

Identification of Mouse MD-2 Residues Important for Forming the Cell Surface TLR4-MD-2 Complex Recognized by Anti-TLR4-MD-2 Antibodies, and for Conferring LPS and Taxol Responsiveness on Mouse TLR4 by Alanine-Scanning Mutagenesis

Kawasaki

Nogawa

Nishijima

2003

The Journal of Immunology

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“…All TLR ligands that were used were checked for potential LPS contamination using a TLR-4 antagonist (E5564), which was kindly provided by Eisai Research Institute, Andover, MA (38). After culture for 48 hours at 37°C in the presence of 5% CO 2 , the supernatants were collected.…”

Section: Methodsmentioning

confidence: 99%

The expression of toll‐like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll‐like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells

Roelofs¹,

Joosten²,

Abdollahi‐Roodsaz³

et al. 2005

Arthritis & Rheumatism

295

219

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Objective. To evaluate the expression of Toll-like receptors (TLRs) 3 and 7 in synovium and to study potential differences in the maturation and cytokine production mediated by TLR-2, TLR-3, TLR-4, and TLR-7/8 by dendritic cells (DCs) from rheumatoid arthritis (RA) patients and DCs from healthy controls.Methods. Synovial expression of TLR-3 and TLR-7 in RA was studied using immunohistochemistry. Monocyte-derived DCs from RA patients and healthy controls were cultured for 6 days and subsequently stimulated for 48 hours via TLR-mediated pathways (lipoteichoic acid, Pam 3 Cys, and fibroblast-stimulating lipopeptide 1 for TLR-2, poly[I-C] for TLR-3, lipopolysaccharide and extra domain A for TLR-4, and R848 for TLR-7/8). Phenotypic DC maturation was measured using flow cytometry. The secretion of tumor necrosis factor ␣ (TNF␣), interleukin-6 (IL-6), IL-10, and IL-12 was measured using the Bio-Plex system. Cell lines expressing TLR-2 and TLR-4 were used for the detection of TLR-2 and TLR-4 ligands in serum and synovial fluid from RA patients.Results. TLR-3 and TLR-7 were highly expressed in RA synovium. All TLR ligands elicited phenotypic DC maturation equally between DCs from RA patients and those from healthy controls. TLR-2-and TLR-4-mediated stimulation of DCs from RA patients resulted in markedly higher production of inflammatory mediators (TNF␣ and IL-6) compared with DCs from healthy controls. In contrast, upon stimulation of TLR-3 and TLR-7/8, the level of cytokine production was equal between DCs from RA patients and those from healthy controls. Remarkably, both TLR-3 and TLR-7/8 stimulation resulted in a skewed balance toward IL-12. Intriguingly, the combined stimulation of TLR-4 and TLR-3-7/8 resulted in a marked synergy with respect to the production of inflammatory mediators. As a proof of concept, TLR-4 ligands were increased in the serum and synovial fluid of RA patients.Conclusion. TLRs are involved in the regulation of DC activation and cytokine production. We hypothesize that various TLR ligands in the joint trigger multiple TLRs simultaneously, favoring the breakthrough of tolerance in RA.

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“…TLR4 appears to interact directly with LPS with the cooperation of LBP (LPS-binding protein) and coreceptors CD14 and MD-2. [90][91][92] Ultimately, LPS sensing by TLR4 leads to the activation of the transcription factor NF-kB and the MAP kinases, JNK and p38, through the activation of two known signaling pathways: a common TLR signaling MyD88-TOLLIP-IRAK-TRAF6 pathway (reviewed in Ref. 71 ) and an MyD88-independent pathway involving the adapter protein TIRAP.…”

Section: Tlr4mentioning

confidence: 99%

Genetic regulation of host responses to Salmonella infection in mice

Malo

2002

Genes Immun

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Salmonella spp are Gram-negative bacteria capable of infecting a wide range of host species, including humans, domesticated and wild mammals, reptiles, birds and insects. The outcome of an encounter between Salmonella and its host is dependent upon multiple factors including the host genetic background. To facilitate the study of the genetic factors involved in resistance to this pathogen, mouse models of Salmonella infection have been developed and studied for years, allowing identification of several genes and pathways that may influence the disease outcome. In this review, we will cover some of the genes involved in mouse resistance to Salmonella that were identified through the study of congenic mouse strains, cloning of spontaneous mouse mutations, use of site-directed mutagenesis or quantitative trait loci analysis. In parallel, the relevant information pertaining to genes involved in resistance to Salmonella in humans will be discussed.

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Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide

Cited by 691 publications

References 42 publications

Identification of Mouse MD-2 Residues Important for Forming the Cell Surface TLR4-MD-2 Complex Recognized by Anti-TLR4-MD-2 Antibodies, and for Conferring LPS and Taxol Responsiveness on Mouse TLR4 by Alanine-Scanning Mutagenesis

Identification of Mouse MD-2 Residues Important for Forming the Cell Surface TLR4-MD-2 Complex Recognized by Anti-TLR4-MD-2 Antibodies, and for Conferring LPS and Taxol Responsiveness on Mouse TLR4 by Alanine-Scanning Mutagenesis

The expression of toll‐like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll‐like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells

Genetic regulation of host responses to Salmonella infection in mice

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