TLR Signaling Pathways: Opportunities for Activation and Blockade in Pursuit of Therapy

Hoebe, Kasper; Jiang, Zuosheng; Georgel, Philippe; Tabeta, Koichi; Janssen, Edwin; Du, Xu; Beutler, Bruce

doi:10.2174/138161206778743466

Cited by 56 publications

(42 citation statements)

References 87 publications

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“…Ncf1 Ϫ/Ϫ mice (produced by J. Roes, University College London, London, U.K.) for the in vivo experiments (provided by A. M. Shah, King's College London, London, U.K.) were backcrossed to C57BL/6 for 10 generations (22,23 (25). Ncf1 mutated mice (Ncf1* / *) with a point mutation in the splice site of exon 8 on a B10.Q background and B10.Q WT mice have previously been described (3).…”

Section: Mice and Spleen Cellsmentioning

confidence: 99%

Ncf1 Provides a Reactive Oxygen Species-Independent Negative Feedback Regulation of TLR9-Induced IL-12p70 in Murine Dendritic Cells

Richter¹,

Juan²,

Will³

et al. 2009

The Journal of Immunology

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Permanent exposure to pathogens requires decisions toward tolerance or immunity as a prime task of dendritic cells. The molecular mechanisms preventing uncontrolled immune responses are not completely clear. We investigated the regulatory function of Ncf1, an organizing protein of NADPH oxidase, in the signaling cascade of Toll-like receptors. TLR9-stimulated spleen cells from both Ncf1-deficient and B10.Q mice with a point mutation in exon 8 of Ncf1 exhibited increased IL-12p70 secretion compared with controls. This finding was restricted to stimulatory CpG2216 and not induced by CpG2088. Because only CpG/TLR9-induced IL-12p70 was regulated by Ncf1, we used TRIF−/− and MyD88−/− cells to show that TLR9/MyD88 was primarily affected. Interestingly, additional experiments revealed that spleen cells from NOX2/gp91phox-deficient mice and the blocking of electron transfer by diphenylene iodonium had no influence on CpG-induced IL-12p70, confirming an NADPH oxidase-independent function of Ncf1. Finally, proving the in vivo relevance CpG adjuvant-guided OVA immunization resulted in a strong augmentation of IL-12p70-dependent Th1 IFN-γ response only in Ncf1-deficient mice. These data suggest for the first time an important role for Ncf1 in the fine tuning of the TLR9/MyD88 pathway in vitro and in vivo that is independent of its role as an activator of NOX2.

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Section: Mice and Spleen Cellsmentioning

confidence: 99%

Ncf1 Provides a Reactive Oxygen Species-Independent Negative Feedback Regulation of TLR9-Induced IL-12p70 in Murine Dendritic Cells

Richter¹,

Juan²,

Will³

et al. 2009

The Journal of Immunology

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“…Major pathways activated by TLR engagement include IκB kinase (IKK) -NFκB, kinase cascades that activate mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinase (PI3K) -Akt. In addition, activation of jun N-terminal kinase (JNK) and p38 MAPK cascades by TLRs result in activation of different activator protein-1 (AP-1) subunits and transcription factors interacting with AP-1 (Chen et al, 2004;Doyle and O'Neill., 2006;Hoebe et al, 2006;Krishnan et al, 2007;Tang et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid β-peptide and the membrane lipid peroxidation product 4-hydroxynonenal

Tang¹,

Lathia²,

Selvaraj³

et al. 2008

Experimental Neurology

219

167

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The innate immune system senses the invasion of pathogenic microorganisms and tissue injury through Toll-like receptors (TLR), a mechanism thought to be limited to immune cells. We recently found that neurons express several TLRs, and that the levels of TLR2 and TLR4 are increased in neurons in response to energy deprivation. Here we report that TLR4 expression increases in neurons when exposed to amyloid β-peptide (Aβ1-42) or the lipid peroxidation product 4-hydroxynonenal (HNE). Neuronal apoptosis triggered by Aβ and HNE was mediated by jun N-terminal kinase (JNK); neurons from TLR4 mutant mice exhibited reduced JNK and caspase-3 activation and were protected against apoptosis induced by Aβ and HNE. Levels of TLR4 were decreased in inferior parietal cortex tissue specimens from end-stage AD patients compared to aged-matched control subjects, possibly as the result of loss of neurons expressing TLR4. Our findings suggest that TLR4 signaling increases the vulnerability of neurons to Aβ and oxidative stress in AD, and identify TLR4 as a potential therapeutic target for AD.

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“…The surfactant protein-A (SP-A) and Toll-like receptor-4 (TLR4) have been identified as important PPRRs (Hoebe et al, 2006;Kawai and Akira, 2007;Kuroki et al, 2007;Pastva et al, 2007). The TLR4 is expressed as transmembrane receptor and is known as a "signaling PPRR" (Kawai and Akira, 2007).…”

Section: Introductionmentioning

confidence: 99%

A Toll-Like Receptor-4-Interacting Surfactant Protein-A-Derived Peptide Suppresses Tumor Necrosis Factor-α Release from Mouse JAWS II Dendritic Cells

Awasthi¹,

Brown²,

King³

et al. 2010

J Pharmacol Exp Ther

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Surfactant protein-A (SP-A) and Toll-like receptor-4 (TLR4) proteins are recognized as pathogen-recognition receptors. An exaggerated activation of TLR4 induces inflammatory response, whereas SP-A protein down-regulates inflammation. We hypothesized that SP-A-TLR4 interaction may lead to inhibition of inflammation. In this study, we investigated interaction between native baboon lung SP-A and baboon and human TLR4-MD2 proteins by coimmunoprecipitation/immunoblotting and microwell-based methods. The interaction between SP-A and TLR4-MD2 proteins was then analyzed using a bioinformatics approach. In the in silico model of SP-A-TLR4 -MD2 complex, we identified potential binding regions and amino acids at the interface of SP-A-TLR4. Using this information, we synthesized a library of human SP-A-derived peptides that contained interacting amino acids. Next, we tested whether the TLR4-interacting SP-A peptides would suppress inflammatory cytokines. The peptides were screened for any changes in the tumor necrosis factor-␣ (TNF-␣) response against lipopolysaccharide (LPS) stimuli in the mouse JAWS II dendritic cell line. Different approaches used in this study suggested binding between SP-A and TLR4-MD2 proteins. In cells pretreated with peptides, three of seven peptides increased TNF-␣ production against LPS. However, two of these peptides (SPA4: GDFRYSDGTPVNYTNWYRGE and SPA5: YVGLTEGPSPGDFRYSDFTP) decreased the TNF-␣ production in LPS-challenged JAWS II dendritic cells; SPA4 peptide showed more pronounced inhibitory effect than SPA5 peptide. In conclusion, we identify a human SP-A-derived peptide (SPA4 peptide) that interacts with TLR4-MD2 protein and inhibits the LPS-stimulated release of TNF-␣ in JAWS II dendritic cells.

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TLR Signaling Pathways: Opportunities for Activation and Blockade in Pursuit of Therapy

Cited by 56 publications

References 87 publications

Ncf1 Provides a Reactive Oxygen Species-Independent Negative Feedback Regulation of TLR9-Induced IL-12p70 in Murine Dendritic Cells

Ncf1 Provides a Reactive Oxygen Species-Independent Negative Feedback Regulation of TLR9-Induced IL-12p70 in Murine Dendritic Cells

Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid β-peptide and the membrane lipid peroxidation product 4-hydroxynonenal

A Toll-Like Receptor-4-Interacting Surfactant Protein-A-Derived Peptide Suppresses Tumor Necrosis Factor-α Release from Mouse JAWS II Dendritic Cells

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