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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Acylation Determines the Toll-like receptor (TLR)-dependent Positive Versus TLR2-, Mannose Receptor-, and SIGNR1-independent Negative Regulation of Pro-inflammatory Cytokines by Mycobacterial Lipomannan
Emilie Doz,Stéphanie Rose,Jérôme Nigou,Martine Gilleron,Germain Puzo,François Erard,Bernhard Ryffel,Valérie F. J. Quesniaux +7 more
TL;DR: It is shown that di-acylated LMs exhibit a potent inhibitory effect on cytokine and NO secretion by LPS-activated macrophages, and may represent an additional mean of regulating the host innate immunity by mycobacteria.
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Differential effects of CpG-DNA in Toll-like receptor-2/-4/-9 tolerance and cross-tolerance
TL;DR: The data indicate that, in contrast to in vitro macrophage desensitization, the in vivo consequences of repeated TLR stimulation greatly differ amongst different TLR ligands.
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The role of innate signaling in the homeostasis of tolerance and immunity in the intestine.
TL;DR: The intestinal epithelium appears to have uniquely evolved to maintain mucosal tolerance and immunity, and future efforts to further understand the molecular mechanisms of intestinal homeostasis may have a major impact on human health.
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Methods for inducing selective apoptosis
TL;DR: In this article, methods for cell therapy by modifying transfused cells to express an inducible caspase 9 protein, so that the cells may be selectively killed if the patient experiences dangerous side effects.
Journal ArticleDOI
A protein associated with toll-like receptor 4 (PRAT4A) regulates cell surface expression of TLR4.
Yasutaka Wakabayashi,Makiko Kobayashi,Sachiko Akashi-Takamura,Natsuko Tanimura,Kazunori Konno,Koichiro Takahashi,Takashi Ishii,Taketoshi Mizutani,Hideo Iba,Taku Kouro,Satoshi Takaki,Kiyoshi Takatsu,Yoshiya Oda,Yasushi Ishihama,Shin-ichiroh Saitoh,Kensuke Miyake +15 more
TL;DR: It is shown here that PRAT4A, a novel protein associated with TLR4, regulates cell surface expression of TLR 4, and knockdown abolished LPS responsiveness in a cell line expressingTLR4/MD-2, probably due to the lack of cell surface TLR3.
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.