Open AccessJournal Article
Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product.
Katsuaki Hoshino,Osamu Takeuchi,Taro Kawai,Hideki Sanjo,Tomohiko Ogawa,Yoshifumi Takeda,Kiyoshi Takeda,Shizuo Akira +7 more
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TLDR
It is demonstrated that TLR4 is the gene product that regulates LPS response, and a single point mutation of the amino acid that is highly conserved among the IL-1/Toll receptor family is found.Abstract:
The human homologue of Drosophila Toll (hToll), also called Toll-like receptor 4 (TLR4), is a recently cloned receptor of the IL-1/Toll receptor family. Interestingly, the TLR4 gene has been localized to the same region to which the Lps locus (endotoxin unresponsive gene locus) is mapped. To examine the role of TLR4 in LPS responsiveness, we have generated mice lacking TLR4. Macrophages and B cells from TLR4-deficient mice did not respond to LPS. All these manifestations were quite similar to those of LPS-hyporesponsive C3H/HeJ mice. Furthermore, C3H/HeJ mice have, in the cytoplasmic portion of TLR4, a single point mutation of the amino acid that is highly conserved among the IL-1/Toll receptor family. Overexpression of wild-type TLR4 but not the mutant TLR4 from C3H/HeJ mice activated NF-κB. Taken together, the present study demonstrates that TLR4 is the gene product that regulates LPS response.read more
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The IκB kinase (IKK) and NF-κB: key elements of proinflammatory signalling
Michael Karin,Mireille Delhase +1 more
TL;DR: There is strong biochemical and genetic evidence that the IKK complex, which consists of two catalytic subunits, IKKα and IKKβ, and a regulatory subunit, Ikkγ, is the master regulator of NF-κB-mediated innate immune and inflammatory responses.
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Toll-like receptor-2 mediates mycobacteria-induced proinflammatory signaling in macrophages.
TL;DR: It is shown that toll-like receptors are required for the induction of TNF-alpha in macrophages by Mycobacterium tuberculosis, and that TLR2-dependent signaling mediates responses to mycobacterial cell wall fractions enriched for lipoarrabinomannan, mycolylarabinogalactan-peptidoglycan complex, or M. tuberculosis total lipids.
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Toll-like Receptors and the Control of Immunity.
TL;DR: The mechanisms and consequences of TLR-mediated signal transduction are described with a focus on themes identified in the TLR pathways that also explain the operation of other immune signaling pathways.
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RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation.
Etienne Meylan,Kim Burns,Kay Hofmann,Vincent Blancheteau,Fabio Martinon,Michelle A. Kelliher,Jürg Tschopp +6 more
TL;DR: This work investigated the 'downstream' signaling events that regulate TLR3-dependent Trif-induced NF-κB activation and found that RIP1 mediates Trif -RIP1–inducedNF-κBs activation.
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Toll-Like Receptors on Hematopoietic Progenitor Cells Stimulate Innate Immune System Replenishment
Yoshinori Nagai,Karla P. Garrett,Shoichiro Ohta,Uleng Bahrun,Taku Kouro,Shizuo Akira,Kiyoshi Takatsu,Paul W. Kincade +7 more
TL;DR: It is shown that TLRs and their coreceptors were expressed by multipotential hematopoietic stem cells, whose cell cycle entry was triggered by TLR ligation, and the preferential pathogen-mediated stimulation of myeloid differentiation pathways may provide a means for rapid replenishment of the innate immune system during infection.
References
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Journal ArticleDOI
Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene
Alexander Poltorak,Xiaolong He,Irina Smirnova,Mu Ya Liu,Christophe Van Huffel,Xin Du,Dale Birdwell,E. Alejos,M. Silva,Chris Galanos,Marina Freudenberg,Paola Ricciardi-Castagnoli,Betsy Layton,Bruce Beutler +13 more
TL;DR: The mammalian Tlr4 protein has been adapted primarily to subserve the recognition of LPS and presumably transduces the LPS signal across the plasma membrane.
Journal Article
Defective LPS signaling in C3 H/HeJ and C57 BL/10 ScCr mice: Mutations in Tlr4 Gene
Alexander Poltorak,Xiaolong He,Irina Smirnova,Mu Ya Liu,C. Van Huffel,Xin Du,Dale Birdwell,E. Alejos,M. Suva,Chris Galanos,Marina Freudenberg,Paola Ricciardi-Castagnoli,B. Layton,Bruce Beutler +13 more
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A human homologue of the Drosophila Toll protein signals activation of adaptive immunity
TL;DR: The cloning and characterization of a human homologue of the Drosophila toll protein (Toll) is reported, which has been shown to induce the innate immune response in adult Dosophila.
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The Dorsoventral Regulatory Gene Cassette spätzle/Toll/cactus Controls the Potent Antifungal Response in Drosophila Adults
TL;DR: It is shown that mutations in the Toll signaling pathway dramatically reduce survival after fungal infection and the intracellular components of the dorsoventral signaling pathway and the extracellular Toll ligand, spätzle, control expression of the antifungal peptide gene drosomycin in adults.
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Innate Immunity: The Virtues of a Nonclonal System of Recognition
TL;DR: Characterization of the nonclonal receptors of the innate immune system responsible for the adjuvant activity, and, evidently, for the associated side effects, would provide a powerful alternative approach, which would ultimately allow one to target these receptors directly.