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Journal ArticleDOI

Toll-like receptor 2-mediated NF-kappa B activation requires a Rac1-dependent pathway.

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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.

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Supernatant from bifidobacterium differentially modulates transduction signaling pathways for biological functions of human dendritic cells.

TL;DR: For the first time, a fermentation product of a bifidobacteria can differentially activate MAPK, GSK3 and PI3K in order to modulate DC biological functions and give new insights on the fine-tuned balance between the maintenance of normal mucosal homeostasis to commensal and probiotic bacteria and the specific inflammatory immune responses to pathogen bacteria.
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Cross-talk between CD14 and complement receptor 3 promotes phagocytosis of mycobacteria: regulation by phosphatidylinositol 3-kinase and cytohesin-1.

TL;DR: Findings reveal that mycobacteria promote their uptake through a process of “inside-out” signaling involving CD14, TLR2, PI3K, and cytohesin-1, which converts low avidity CR3 into an active receptor leading to increased bacterial internalization.
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Molecular Aspects of Moraxella catarrhalis Pathogenesis

TL;DR: A timely overview of the current understanding of the molecular mechanisms associated with M. catarrhalis virulence and pathogenesis is provided.
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YopH prevents monocyte chemoattractant protein 1 expression in macrophages and T-cell proliferation through inactivation of the phosphatidylinositol 3-kinase pathway.

TL;DR: Using single knock‐out mutants in bacterial effector genes, it is determined that the tyrosine phosphatase YopH was responsible for the inactivation of the PI 3‐kinase cascade, and in macrophages, this inactivation correlated with the downregulation of mRNA coding for monocyte chemoattractant protein 1 (MCP‐1), suggesting that Yop H inhibits recruitment of macrophage to lymph nodes.
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A modulatory interleukin-10 response to staphylococcal peptidoglycan prevents Th1/Th17 adaptive immunity to Staphylococcus aureus.

TL;DR: It is shown that the modulatory IL-10 response preferentially occurs upon CD14- and CD36-independent TLR2 signaling, triggering PI3K activation, and is restricted to monocytes and monocyte-derived macrophages (MΦs), whereas DCs trigger a robust Th1/Th17 response.
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.

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

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

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.
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