Toll-like récepteurs

Essakalli, M.; Atouf, O.; Bennani, N.; Benseffaj, N.; Ouadghiri, S.; Brick, C.

doi:10.1016/j.patbio.2008.04.003

Cited by 14 publications

(15 citation statements)

References 22 publications

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“…These adaptors include myeloid differentiation factor 88 (MyD88), MyD88 adaptor-like protein (Mal), TIR-containing adaptor inducing IFNβ (TRIF), also known as TIRAP-1 (TICAM-1), and TRIF-related adaptor molecule (TRAM). Activation of TLR4 leads to stimulation of both MyD88-dependent and MyD88-independent pathways [19]. Moreover, in HRMCs, we showed that LPS-induced VCAM-1 expression was inhibited by transfection with MyD88 siRNA (Figure 1E).…”

Section: Resultsmentioning

confidence: 87%

“…On the other hand, we demonstrated that LPS could directly induce TLR4 mRNA expression in a time-dependent manner in HRMCs (Figure 1D). The TLR4 signaling cascade initiated following LPS binding is enhanced by homodimerization of the receptor and subsequent recruitment of TIR domain-containing adaptor molecules (TIRAP) to the cytoplasmic domain of the receptor [19]. These adaptors include myeloid differentiation factor 88 (MyD88), MyD88 adaptor-like protein (Mal), TIR-containing adaptor inducing IFNβ (TRIF), also known as TIRAP-1 (TICAM-1), and TRIF-related adaptor molecule (TRAM).…”

Section: Resultsmentioning

confidence: 99%

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Role of TLR4/NADPH oxidase/ROS-activated p38 MAPK in VCAM-1 expression induced by lipopolysaccharide in human renal mesangial cells

et al. 2012

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BackgroundIn bacteria-induced glomerulonephritis, Toll-like receptor 4 (TLR4) activation by lipopolysaccharide (LPS, a key component of the outer membranes of Gram-negative bacteria) can increase oxidative stress and the expression of vascular cell adhesion molecule-1 (VCAM-1), which recruits leukocytes to the glomerular mesangium. However, the mechanisms underlying VCAM-1 expression induced by LPS are still unclear in human renal mesangial cells (HRMCs).ResultsWe demonstrated that LPS induced VCAM-1 mRNA and protein levels associated with an increase in the promoter activity of VCAM-1, determined by Western blot, RT-PCR, and promoter assay. LPS-induced responses were inhibited by transfection with siRNAs of TLR4, myeloid differentiation factor 88 (MyD88), Nox2, Nox4, p47phox, c-Src, p38 MAPK, activating transcription factor 2 (ATF2), and p300 or pretreatment with the inhibitors of reactive oxygen species (ROS, edaravone), NADPH oxidase [apocynin (APO) or diphenyleneiodonium chloride (DPI)], c-Src (PP1), p38 MAPK (SB202190), and p300 (GR343). LPS induced NADPH oxidase activation, ROS production, and p47phox translocation from the cytosol to the membrane, which were reduced by PP1 or c-Src siRNA. We observed that LPS induced TLR4, MyD88, c-Src, and p47phox complex formation determined by co-immunoprecipitation and Western blot. We further demonstrated that LPS stimulated ATF2 and p300 phosphorylation and complex formation via a c-Src/NADPH oxidase/ROS/p38 MAPK pathway. Up-regulation of VCAM-1 led to enhancing monocyte adhesion to HRMCs challenged with LPS, which was inhibited by siRNAs of c-Src, p47phox, p38 MAPK, ATF2, and p300 or pretreatment with an anti-VCAM-1 neutralizing antibody.ConclusionsIn HRMCs, LPS-induced VCAM-1 expression was, at least in part, mediated through a TLR4/MyD88/ c-Src/NADPH oxidase/ROS/p38 MAPK-dependent p300 and ATF2 pathway associated with recruitment of monocyte adhesion to kidney. Blockade of these pathways may reduce monocyte adhesion via VCAM-1 suppression and attenuation of the inflammatory responses in renal diseases.

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Section: Resultsmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Role of TLR4/NADPH oxidase/ROS-activated p38 MAPK in VCAM-1 expression induced by lipopolysaccharide in human renal mesangial cells

et al. 2012

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“…TLR4 signaling cascade is initiated by the co-receptor CD14, following interaction of LPS with LPS binding protein (LBP). The receptor signaling is enhanced by its mono-dimerization followed by recruitment of adaptor proteins and kinases to the intracellular TIR domain of the receptor [26, 27]. The cytosolic adapter proteins including myeloid differentiation primary response protein 88 (MyD88), TIR adaptor protein (TIRAP), and tumor necrotic factor receptor-associated factor 6 (TRAF6) [28] initiate the proximal events of TLR4-mediated intracellular signaling.…”

Section: Introductionmentioning

confidence: 99%

Activation of c-Src: A hub for exogenous pro-oxidant-mediated activation of Toll-like receptor 4 signaling

Karki

Zhang

Igwe

2014

Free Radical Biology and Medicine

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Summary To study the role of c-Src kinase in prooxidant-induced stimulation of TLR4, we used LPS-EK and MPLA as TLR4 specific agonists and positive controls, and SIN-1 and PPC as prooxidant sources. We used HEK-Blue mTLR4 cell line that is stably transfected with mouse TLR4 and that expresses optimized SEAP reporter under the control of a promoter inducible by NF-κB transcription factor. The level of SEAP released due to TLR4 stimulation was a measure of NF-κB activation. Treatment with either the prooxidants or LPS-EK increased SEAP release and TNF-α production in these cells. These treatments also increased intracellular ROS accumulation with an enhanced production of nitric oxide and TBARS to confirm oxidant stress in these cells. Pretreatment with c-Src kinase inhibitors, PP2 and CA-pY, which act by different mechanisms, decreased these parameters. Pretreatment with SSG, a c-Src activator, enhanced the effects promoted by LPS-EK and prooxidants, and rescued cells from PP2- and Ca-pY-induced effects. Curiously, prooxidants but not TLR4 agonist increased the ratio of TNFα to IL-10 released suggesting that prooxidants can initiate and maintain an imbalance of TNFα production over IL-10. To different degrees, both prooxidant and TLR4 agonist increased formation of c-Src complexes with TLR4 and IκB-α as coimmunoprecipitates. Both prooxidant and TLR4 agonist increased c-Src phosphorylation of Tyr-42 residue in IκB-α, but prooxidant-induced effect was more robust and much longer lasting. Taken together, these studies provide a mechanism whereby c-Src assumes a central role in prooxidant-induced NF-κB activation in TLR4 signaling. Prooxidant-induced activation of TLR4 through c-Src/NFκB/IκB-α coupling provides a basis for a molecular dissection of the initiation and maintenance of sterile inflammation that may serve as a “pathophysiologic primer” for many diseases.

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“…Thus, when microorganisms are detected, TLRs are engaged and subsequently trigger activation of the innate immune system, discriminating between specific patterns of microbial agents [7,[11][12][13]. Upon activation, TLR activates two major signaling pathways: (1) one pathway leading to the activation of the two transcription factors Nuclear Factor-KappaB (NF-B) and Interferon Regulatory Factor-3 (IRF3); and (2) another pathway leading to the activation of NF-B and the MitogenActivated Protein Kinases (MAPKs) p38 and c-Jun Kinase (JNK), Fig. (1) [14][15][16][17].…”

Section: Summary Of the Toll-like Receptor Signaling Pathwaymentioning

confidence: 99%

“…The innate immune system can be inactivated by disruption in associate proteins that interact with TLRs and subsequent signaling proteins downstream. Over the past several years, a number of TLR genes have been identified and characterized, and the successive number of such genes being discovered continues to fill a void in immunology [1][2][3][4]. TLRs and associate genes have been designated according to their appropriate ligand and immune response.…”

Section: Introductionmentioning

confidence: 99%

Recent Patents in Toll-like Receptor Pathways and Relevance to Cancer

Kimbro

Parker²

2009

PRA

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The first lines of defense in the human innate immune system are membrane receptors called Toll-like receptors (TLRs). This family of receptors functions as primary sensors to recognize microbial pathogens. Subsequent binding of ligands to TLRs lend to the activation of cellular signaling pathways that regulate expression of genes related to inflammation and immunity. The discovery and supporting evidence of functional and structural diversity suggests TLRs are key participants in cellular immunity and are important to various medical conditions including the tumor microenvironment. TLR heterogeneity emphasizes the role of these receptors and suggests a new opportunity to develop therapies targeting specific or multiple TLRs that may contribute to the treatment of a myriad of diseases including various cancers. In this article, we intend to focus on a number of recently issued patents related to TLRs and to propose the relevance of these patents to novel treatments for cancers.

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Toll-like récepteurs

Cited by 14 publications

References 22 publications

Role of TLR4/NADPH oxidase/ROS-activated p38 MAPK in VCAM-1 expression induced by lipopolysaccharide in human renal mesangial cells

Role of TLR4/NADPH oxidase/ROS-activated p38 MAPK in VCAM-1 expression induced by lipopolysaccharide in human renal mesangial cells

Activation of c-Src: A hub for exogenous pro-oxidant-mediated activation of Toll-like receptor 4 signaling

Recent Patents in Toll-like Receptor Pathways and Relevance to Cancer

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