Differential Induction of the Toll-Like Receptor 4-MyD88-Dependent and -Independent Signaling Pathways by Endotoxins
Susu M. Zughaier,Shanta M. Zimmer,Anup Datta,Russell W. Carlson,David S. Stephens,David S. Stephens +5 more
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Neisseria meningitidis endotoxin was a potent agonist of both the MyD88-dependent and -independent signaling pathways of the TLR4 receptor complex of human macrophages and response was restored inTLR4-MD-2-transfected human embryonic kidney 293 cells.Abstract:
The biological response to endotoxin mediated through the Toll-like receptor 4 (TLR4)-MD-2 receptor complex is directly related to lipid A structure or configuration Endotoxin structure may also influence activation of the MyD88-dependent and -independent signaling pathways of TLR4 To address this possibility, human macrophage-like cell lines (THP-1, U937, and MM6) or murine macrophage RAW 2647 cells were stimulated with picomolar concentrations of highly purified endotoxins Harvested supernatants from previously stimulated cells were also used to stimulate RAW 2647 or 23ScCr (TLR4-deficient) macrophages (ie, indirect induction) Neisseria meningitidis lipooligosaccharide (LOS) was a potent direct inducer of the MyD88-dependent pathway molecules tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 3alpha (MIP-3alpha), and the MyD88-independent molecules beta interferon (IFN-beta), nitric oxide, and IFN-gamma-inducible protein 10 (IP-10) Escherichia coli 55:B5 and Vibrio cholerae lipopolysaccharides (LPSs) at the same pmole/ml lipid A concentrations induced comparable levels of TNF-alpha, IL-1beta, and MIP-3alpha, but significantly less IFN-beta, nitric oxide, and IP-10 In contrast, LPS from Salmonella enterica serovars Minnesota and Typhimurium induced amounts of IFN-beta, nitric oxide, and IP-10 similar to meningococcal LOS but much less TNF-alpha and MIP-3alpha in time course and dose-response experiments No MyD88-dependent or -independent response to endotoxin was seen in TLR4-deficient cell lines (C3H/HeJ and 23ScCr) and response was restored in TLR4-MD-2-transfected human embryonic kidney 293 cells Blocking the MyD88-dependent pathway by DNMyD88 resulted in significant reduction of TNF-alpha release but did not influence nitric oxide release IFN-beta polyclonal antibody and IFN-alpha/beta receptor 1 antibody significantly reduced nitric oxide release N meningitidis endotoxin was a potent agonist of both the MyD88-dependent and -independent signaling pathways of the TLR4 receptor complex of human macrophages E coli 55:B5 and Vibrio cholerae LPS, at the same picomolar lipid A concentrations, selectively induced the MyD88-dependent pathway, while Salmonella LPS activated the MyD88-independent pathwayread more
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Epidemic meningitis, meningococcaemia, and Neisseria meningitidis.
TL;DR: The next generation of meningococcal conjugate vaccines for serogroups A, C, Y, W-135, and broadly effective serogroup B vaccines are on the horizon, which could eliminate the organism as a major threat to human health in industrialised countries in the next decade.
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Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors.
TL;DR: The availability of endogenous ligands and the amount of cell surface TLRs are both tightly limited to keep TLR responses sufficient for containment of pathogens without detrimental responses to the host.
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The Cytosolic Sensor cGAS Detects Mycobacterium tuberculosis DNA to Induce Type I Interferons and Activate Autophagy
Robert O. Watson,Samantha L. Bell,Donna A. MacDuff,Jacqueline M. Kimmey,Elie J. Diner,Joanna Olivas,Russell E. Vance,Christina L. Stallings,Herbert W. Virgin,Jeffery S. Cox +9 more
TL;DR: It is reported that the cytosolic DNA sensor, cyclic GMP-AMP synthase (cGAS), is required for activating IFN production via the STING/TBK1/IRF3 pathway during M. tuberculosis and L. pneumophila infection of macrophages, whereas L. monocytogenes short-circuits this pathway by producing the STing agonist, c-di-AMP.
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Induction of the interferon response by siRNA is cell type- and duplex length-dependent.
Angela Reynolds,Emily M. Anderson,Annaleen Vermeulen,Yuriy Fedorov,Kathryn Robinson,Devin Leake,Jon Karpilow,William Marshall,Anastasia Khvorova +8 more
TL;DR: It is demonstrated that >23-bp ds RNA can influence cell viability and induce a potent IFN response (highlighted by a strong up-regulation of the dsRNA receptor, Toll-like receptor 3) in a cell type-specific manner, suggesting that the length threshold for siRNA induction of theIFN response is not fixed but instead varies significantly among different cell types.
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Structural biology of the LPS recognition
TL;DR: The proposed mechanism of L PS recognition by the innate immune system involves as the first step binding of the LPS-binding protein (LBP) to LPS, which leads to a disruption of LPS aggregates Cationic amino acid residues at the tip of LBP play the most important role
References
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Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway.
Masahiro Yamamoto,Shintaro Sato,Hiroaki Hemmi,Katsuaki Hoshino,Tsuneyasu Kaisho,Hideki Sanjo,Osamu Takeuchi,Masanaka Sugiyama,Masaru Okabe,Kiyoshi Takeda,Shizuo Akira +10 more
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Tlr signaling pathways
Kiyoshi Takeda,Shizuo Akira +1 more
TL;DR: Toll-like receptors have been established to play an essential role in the activation of innate immunity by recognizing specific patterns of microbial components and TIR domain-containing adaptors provide specificity of TLR signaling.
Journal ArticleDOI
Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction
Katherine A. Fitzgerald,Eva M. Palsson-McDermott,Andrew G. Bowie,Andrew G. Bowie,Caroline A. Jefferies,Ashley Mansell,Gerard Brady,Elizabeth Brint,Aisling Dunne,Pearl Gray,Mary T. Harte,Diane McMurray,Dirk E. Smith,John E. Sims,T. A. Bird,Luke A. J. O'Neill +15 more
TL;DR: A protein is described, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TIR-domain-containing protein in the human genome, which is therefore an adapter in TLR-4 signal transduction.
Journal ArticleDOI
Identification of Lps2 as a key transducer of MyD88-independent TIR signalling.
Kasper Hoebe,Xin Du,Philippe Georgel,Edith M. Janssen,Koichi Tabeta,Sung Ouk Kim,Jason Goode,Pei Lin,Navjiwan Mann,Suzanne Mudd,Karine Crozat,Sosathya Sovath,Jiahuai Han,Bruce Beutler +13 more
TL;DR: Using N-ethyl-N-nitrosourea, a germline mutation is induced called Lps2, which abolishes cytokine responses to double-stranded RNA and severely impairs responses to the endotoxin lipopolysaccharide (LPS), indicating that TLR3 and TLR4 might share a specific, proximal transducer.
Journal ArticleDOI
TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction.
TL;DR: This work has identified an alternative adaptor, designated Toll-interleukin 1 receptor domain (TIR)-containing adaptor molecule (TICAM)-1, that can physically bind the TIR domain of TLR3 and activate the IFN-β promoter in response to poly(I):poly(C).