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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A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release
Huan Yang,Hulda Sigridur Hreggvidsdottir,Karin Palmblad,Haichao Wang,Mahendar Ochani,Jianhua Li,Ben Lu,Sangeeta S. Chavan,Mauricio Rosas-Ballina,Yousef Al-Abed,Shizuo Akira,Angelika Bierhaus,Helena Erlandsson-Harris,Ulf Andersson,Kevin J. Tracey +14 more
TL;DR: It is shown that Toll-like receptor 4 (TLR4), a pivotal receptor for activation of innate immunity and cytokine release, is required for HMGB1-dependent activation of macrophage TNF release.
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Toll-like receptor–mediated NF-κB activation: a phylogenetically conserved paradigm in innate immunity
Guolong Zhang,Sankar Ghosh +1 more
TL;DR: The role of the conserved TLR/NF-κB signaling pathway in innate immunity, as well as its impact on adaptive immune responses, is focused on.
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Receptors, Mediators, and Mechanisms Involved in Bacterial Sepsis and Septic Shock
TL;DR: The role of individual receptors such as the toll-like receptors and CD14 in the induction of proinflammatory cytokines and adhesion molecules is discussed in detail in this article, and the roles of other receptors that bind bacterial compounds such as scavenger receptors and their modulating role in inflammation are described.
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Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster
TL;DR: A new model of LPS recognition is proposed, based on the discovery of the TLRs and the LPS-activation cluster, which comprises heat-shock proteins (Hsps) 70 and 90, chemokine receptor 4 (CXCR4) and growth differentiation factor 5 (GDF5).
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Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells
Fabio Re,Jack L. Strominger +1 more
TL;DR: It is demonstrated that activation of dendritic cells by TLR2 or TLR4 agonists, although it led to comparable activation of NF-κB and mitogen-activated protein kinase (MAPK) family members, resulted in striking differences in cytokine and chemokine gene transcription, suggesting that TLR 2 andTLR4 signaling is not equivalent.
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.