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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GEF-H1 Mediated Control of NOD1 Dependent NF-κB Activation by Shigella Effectors
Atsuko Fukazawa,Carmen Alonso,Kiyotaka Kurachi,Sonal Gupta,Cammie F. Lesser,Beth A. McCormick,Hans Christian Reinecker +6 more
TL;DR: It is demonstrated that GEF-H1 is a critical component of cellular defenses forming an intracellular sensing system with NOD1 for the detection of microbial effectors during cell invasion by pathogens.
Journal ArticleDOI
Mal connects TLR2 to PI3Kinase activation and phagocyte polarization
Sandra Santos-Sierra,Sachin D. Deshmukh,Julia Kalnitski,Peter Küenzi,Matthias P. Wymann,Douglas T. Golenbock,Philipp Henneke +6 more
TL;DR: A novel‐signalling pathway downstream of TLR2, which does not adhere to the established model is reported here on, which connectsTLR2/6 to PI3K activation, PIP3 generation and macrophage polarization.
Journal ArticleDOI
CD36 and TLR Interactions in Inflammation and Phagocytosis: Implications for Malaria
Laura K. Erdman,Gabriela Cosío,Andrew Helmers,D. Channe Gowda,Sergio Grinstein,Kevin C. Kain,Kevin C. Kain +6 more
TL;DR: It is shown that selective engagement and internalization of this receptor did not lead to proinflammatory cytokine production by primary human and murine macrophages, and that CD36 must cooperate with other receptors such as TLRs to participate in cytokine responses.
Journal ArticleDOI
TLR2 ligands induce cardioprotection against ischaemia/reperfusion injury through a PI3K/Akt-dependent mechanism
Tuanzhu Ha,Yulong Hu,Li Liu,Chen Lu,Julie R. McMullen,Jim Kelley,Race L. Kao,David L. Williams,Xiang Gao,Chuanfu Li +9 more
TL;DR: It is demonstrated thatTLR2 ligands induced cardioprotection, which is mediated through a TLR2/PI3K/Akt-dependent mechanism, which was lost in TLR 2-deficient mice.
Journal ArticleDOI
Convergence of the Mammalian Target of Rapamycin Complex 1- and Glycogen Synthase Kinase 3-β–Signaling Pathways Regulates the Innate Inflammatory Response
Huizhi Wang,Jonathan Brown,Zhen Gu,Carlos A. Garcia,Ruqiang Liang,Pascale Alard,Eléonore Beurel,Richard S. Jope,Terrance Greenway,Michael Martin +9 more
TL;DR: It is shown that m TORC1 and GSK3-β converge and that the capacity of mTORC1 to affect the inflammatory response is due to the inactivation of GSK 3-β, and that mTorC1 inhibition regulates pro- and anti-inflammatory cytokine production via its capacity to inactivate G SK3.
References
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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.
Journal ArticleDOI
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.