Journal ArticleDOI
Toll-like receptor 2-mediated NF-kappa B activation requires a Rac1-dependent pathway.
Laurence Arbibe,Jean Paul Mira,Jean Paul Mira,Nicole Teusch,Lois Kline,Mausumee Guha,Nigel Mackman,Paul J. Godowski,Richard J. Ulevitch,Ulla G. Knaus +9 more
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TLDR
TLR2 stimulation by Staphylococcus aureus induces a fast and transient activation of the Rho GTPases Rac1 and Cdc42 in the human monocytic cell line THP-1 and in 293 cells expressing TLR2, and Rac1 controls a second, IκB–independent, pathway to NF-κB activation and is essential in innate immune cell signaling via TLR 2.Abstract:
Mammalian Toll-like receptors (TLRs) are expressed on innate immune cells and respond to the membrane components of Gram-positive or Gram-negative bacteria. When activated, they convey signals to transcription factors that orchestrate the inflammatory response. However, the intracellular signaling events following TLR activation are largely unknown. Here we show that TLR2 stimulation by Staphylococcus aureus induces a fast and transient activation of the Rho GTPases Rac1 and Cdc42 in the human monocytic cell line THP-1 and in 293 cells expressing TLR2. Dominant-negative Rac1N17, but not dominant-negative Cdc42N17, block nuclear factor-κB (NF-κB) transactivation. S. aureus stimulation causes the recruitment of active Rac1 and phosphatidylinositol-3 kinase (PI3K) to the TLR2 cytosolic domain. Tyrosine phosphorylation of TLR2 is required for assembly of a multiprotein complex that is necessary for subsequent NF-κB transcriptional activity. A signaling cascade composed of Rac1, PI3K and Akt targets nuclear p65 transactivation independently of IκBα degradation. Thus Rac1 controls a second, IκB–independent, pathway to NF-κB activation and is essential in innate immune cell signaling via TLR2.read more
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Response to Staphylococcus aureus requires CD36-mediated phagocytosis triggered by the COOH-terminal cytoplasmic domain
Lynda M. Stuart,Jiusheng Deng,Jessica M. Silver,Kazue Takahashi,Anita A. Tseng,Elizabeth J. Hennessy,R. Alan B. Ezekowitz,Kathryn J. Moore +7 more
TL;DR: In this article, the Drosophila melanogaster scavenger receptor Croquemort was identified as a receptor for Staphylococcus aureus, implicating for the first time the CD36 family as phagocytic receptors for bacteria.
Journal ArticleDOI
IFN-γ Suppresses IL-10 Production and Synergizes with TLR2 by Regulating GSK3 and CREB/AP-1 Proteins
Xiaoyu Hu,Paul K. Paik,Janice Chen,Anna Yarilina,Lisa Kockeritz,Theresa T. Lu,James R. Woodgett,Lionel B. Ivashkiv,Lionel B. Ivashkiv +8 more
TL;DR: IFN-gamma augments induction of TNFalpha by TLR ligands, immune complexes, and zymosan by suppressing IL-10 production and thereby interrupting Stat3-mediated feedback inhibition, and identifies inhibition of CREB and AP-1 as part of the macrophage response to IFN-Gamma.
Journal ArticleDOI
Zinc as a Gatekeeper of Immune Function
TL;DR: Molecular mechanisms underlying the development of a pro-inflammatory phenotype during zinc deficiency are reported, and links between altered zinc homeostasis and disease development are described, ensuring the benefits of zinc supplementation for a malfunctioning immune system become clear.
Journal ArticleDOI
Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands
Xiaoxia Z. West,Nikolay L. Malinin,Alona Merkulova,Mira Tischenko,Bethany A. Kerr,Ernest C. Borden,Eugene A. Podrez,Robert G. Salomon,Tatiana V. Byzova +8 more
TL;DR: These findings establish a new function of TLR2 as a sensor of oxidation-associated molecular patterns, providing a key link connecting inflammation, oxidative stress, innate immunity and angiogenesis.
Journal ArticleDOI
Minimally modified LDL binds to CD14, induces macrophage spreading via TLR4/MD-2, and inhibits phagocytosis of apoptotic cells.
Yury I. Miller,Suganya Viriyakosol,Christoph J. Binder,James R. Feramisco,Theo N. Kirkland,Joseph L. Witztum +5 more
TL;DR: It is demonstrated that mmLDL induces actin polymerization and spreading of macrophages, which results in such pro-atherogenic consequences as inhibition of phagocytosis of apoptotic cells but enhancement of OxLDL uptake.
References
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Journal ArticleDOI
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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Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components.
Osamu Takeuchi,Katsuaki Hoshino,Taro Kawai,Hideki Sanjo,Haruhiko Takada,Tomohiko Ogawa,Kiyoshi Takeda,Shizuo Akira +7 more
TL;DR: It is demonstrated that TLR2 and TLR4 recognize different bacterial cell wall components in vivo andTLR2 plays a major role in Gram-positive bacterial recognition.
Journal ArticleDOI
Toll-like receptors in the induction of the innate immune response
Alan Aderem,Richard J. Ulevitch +1 more
TL;DR: A group of proteins that comprise the Toll or Toll-like family of receptors perform this role in vertebrate and invertebrate organisms and it is therefore not surprising that studies of the mechanism by which they act has revealed new and important insights into host defence.
Journal ArticleDOI
Rho GTPases and signaling networks
TL;DR: The Rho GTPases form a subgroup of the Ras superfamily of 20- to 30-kD GTP-binding proteins that have been shown to regulate a wide spectrum of cellular functions, and some of the more recent exciting findings hinting at novel, unanticipated functions of the RhoGTPases are summarized.
Journal ArticleDOI
NF-κB activation by tumour necrosis factor requires the Akt serine–threonine kinase
Osman N. Ozes,Lindsey D. Mayo,Jason A. Gustin,Susan R. Pfeffer,Lawrence M. Pfeffer,David B. Donner +5 more
TL;DR: It is shown that the Akt serine–threonine kinase is involved in the activation of NF-κB by tumour necrosis factor (TNF), and that Akt is part of a signalling pathway that is necessary for inducing key immune and inflammatory responses.