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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Src-family-tyrosine kinase Lyn is critical for TLR2-mediated NF-κB activation through the PI 3-kinase signaling pathway.
Julie Toubiana,Anne-Lise Rossi,Nadia Belaïdouni,David Grimaldi,Frédéric Pène,Philippe Chafey,Béatrice Comba,Luc Camoin,Georges Bismuth,Yann-Erick Claessens,Jean-Paul Mira,Jean-Daniel Chiche,Jean-Daniel Chiche +12 more
TL;DR: Lyn kinase activity is crucial in TLR2-mediated activation of the innate immune response in human mononuclear cells by using complementary inhibition strategies.
Journal ArticleDOI
The rLrp of Mycobacterium tuberculosis inhibits proinflammatory cytokine production and downregulates APC function in mouse macrophages via a TLR2-mediated PI3K/Akt pathway activation-dependent mechanism
TL;DR: The inhibitory effects of rLrp were dependent on TLR2-mediated activation of the phosphatidylinositol 3-OH kinase (PI3K)/Akt pathway, and the possibility that mimetic inhibitory peptides could be used to restrict innate immune responses in situations in which prolonged TLR signaling has deleterious effects is raised.
Journal ArticleDOI
Targeting of host-cell ubiquitin and ubiquitin-like pathways by bacterial factors
Laurent Boyer,Emmanuel Lemichez +1 more
TL;DR: Given the growing implication of ULPs in cell signalling, autophagy and membrane trafficking, there is little doubt that further examples of direct or indirect interactions between bacterial factors and ULPs will be documented.
Journal ArticleDOI
Myeloid Differentiation Factor-2 Interacts with Lyn Kinase and Is Tyrosine Phosphorylated Following Lipopolysaccharide-Induced Activation of the TLR4 Signaling Pathway
Pearl Gray,Jargalsaikhan Dagvadorj,Kathrin S. Michelsen,Constantinos Brikos,Altan Rentsendorj,Terrence Town,Terrence Town,Timothy R. Crother,Moshe Arditi +8 more
TL;DR: It is demonstrated that tyrosine phosphorylation of MD-2 is important for signaling following exposure to LPS and underscores the importance of this event in mediating an efficient and prompt immune response.
Journal ArticleDOI
Protein tyrosine phosphatase SHP-1 positively regulates TLR-induced IL-12p40 production in macrophages through inhibition of phosphatidylinositol 3-kinase.
TL;DR: There is a critical role for the tyrosine phosphatase activity of SHP‐1 for induction of IL‐12p40 production in macrophages in response to TLR ligands, a novel mechanism for host regulation of a specific proinflammatory cytokine important in both innate and adaptive immunity.
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.