Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

TLR 4 Signaling Inhibitory Pathway Induced by Green Tea Polyphenol Epigallocatechin-3-Gallate through 67-kDa Laminin Receptor

ABSTRACT: Epigallocatechin-3-gallate (EGCG), a major active polyphenol of green tea, has been shown to downregulate inflammatory responses in macrophages; however, the underlying mechanism has not been understood. Recently, we identified the 67-kDa laminin receptor (67LR) as a cell-surface EGCG receptor that mediates the anti-cancer action of EGCG at physiologically relevant concentrations (0.1-1 mM). Here we show the molecular basis for the downregulation of TLR4 signal transduction by EGCG at 1 mM in macrophages. Anti-67LR antibody treatment or RNAi-mediated silencing of 67LR resulted in abrogation of the inhibitory action of EGCG on LPS-induced activation of downstream signaling pathways and target gene expressions. Additionally, we found that EGCG reduced the TLR4 expression through 67LR. Interestingly, EGCG induced a rapid upregulation of Tollip protein, a negative regulator of TLR-signaling, and this EGCG action was prevented by 67LR silencing or anti-67LR antibody treatment. RNAi-mediated silencing of Tollip impaired the TLR4 signaling inhibitory activity of EGCG. Taken together, these findings demonstrate that 67LR plays a critical role in mediating anti-inflammatory action of a physiologically relevant EGCG and Tollip expression could be modulated through 67LR. These results provide a new insight into the understanding of negative regulatory mechanisms for TLR4 signaling pathway and consequent inflammatory responses which are implicated in the development and progression of many chronic diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE21320 | GEO | 2010/04/20

SECONDARY ACCESSION(S): PRJNA126329

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

TLR 4 Signaling Inhibitory Pathway Induced by Green Tea Polyphenol Epigallocatechin-3-Gallate through 67-kDa Laminin Receptor

Project description:Epigallocatechin-3-gallate (EGCG), a major active polyphenol of green tea, has been shown to downregulate inflammatory responses in macrophages; however, the underlying mechanism has not been understood. Recently, we identified the 67-kDa laminin receptor (67LR) as a cell-surface EGCG receptor that mediates the anti-cancer action of EGCG at physiologically relevant concentrations (0.1-1 mM). Here we show the molecular basis for the downregulation of TLR4 signal transduction by EGCG at 1 mM in macrophages. Anti-67LR antibody treatment or RNAi-mediated silencing of 67LR resulted in abrogation of the inhibitory action of EGCG on LPS-induced activation of downstream signaling pathways and target gene expressions. Additionally, we found that EGCG reduced the TLR4 expression through 67LR. Interestingly, EGCG induced a rapid upregulation of Tollip protein, a negative regulator of TLR-signaling, and this EGCG action was prevented by 67LR silencing or anti-67LR antibody treatment. RNAi-mediated silencing of Tollip impaired the TLR4 signaling inhibitory activity of EGCG. Taken together, these findings demonstrate that 67LR plays a critical role in mediating anti-inflammatory action of a physiologically relevant EGCG and Tollip expression could be modulated through 67LR. These results provide a new insight into the understanding of negative regulatory mechanisms for TLR4 signaling pathway and consequent inflammatory responses which are implicated in the development and progression of many chronic diseases. We quantified expression profile of 210 inflammatory-relating genes in the 67LR-downregulated cells treated with LPS or/and EGCG by microarray

2010-04-20 | E-GEOD-21320 | biostudies-arrayexpress

Mus musculus

Project description:Creation of an anti-inflammatory GR cistrome by TLR4 signaling

| PRJNA145469 | ENA

Mus musculus

Project description:Creation of an anti-inflammatory GR cistrome by TLR4 signaling

| PRJNA145263 | ENA

The role of topical containing camellia sinensis in the cosmetic management of skin scars in healthy human volunteers

Project description:Epigallocatechin-3-gallate (EGCG), a polyphenol, influences cutaneous wound healing due to its anti-angiogenic, anti-inflammatory and anti-oxidant properties. We previously demonstrated the role of EGCG in scarring in ex vivo human scar models. A double-blind randomised-controlled trial. Here, we evaluated application of topical EGCG compared with placebo in 62 healthy human volunteers, over 8 weeks, in scars created in their upper inner arms using skin punch biopsies. RNA sequencing was used here based on 45 samples: day 0 (n=3), week 1 (n=3 placebo, n=3 EGCG), week 2 (n=3 placebo, n=3 EGCG), week 3 (n=3 placebo, n=3 EGCG), week 4 (n=3 placebo, n=3 EGCG), week 5 (n=3 placebo, n=3 EGCG), week 6 (n=3 placebo, n=3 EGCG), week 8 (n=3 placebo, n=3 EGCG). The common differentially expressed genes identified between treated (EGCG) and placebo samples were grouped according to time point (Zonal priming: weeks 1 and 2; Direct application post scar formation (2 weeks post-biopsies): weeks 1, 2, 3, 4, 6). Further exploration of these genes using Gene Ontology and Ingenuity Pathway Analysis revealed gene signatures of relevant biological processes and pathways. Here, RNA sequencing revealed a number of angiogenic, inflammatory and antioxidant genes that were significantly downregulated with EGCG particularly at week 1 including; TPSAB1, VEGFA, EDF, IL17F, IL1A, IL1RL1, IL36A, IL36G, SOD3.

2019-05-01 | GSE124161 | GEO

The role of topical containing camellia sinensis in the cosmetic management of skin scars in healthy human volunteers: part 2

Project description:Epigallocatechin-3-gallate (EGCG), a polyphenol, influences cutaneous wound healing due to its anti-angiogenic, anti-inflammatory and anti-oxidant properties. We previously showed EGCG is effective in improving skin scarring when applied immediately post-injury. Here, this double-blinded randomized placebo-controlled trial compared the effects of pre-emptive priming versus immediate and delayed topical EGCG compared with placebo. This was evaluated in 40 healthy human volunteers, over 8 weeks, in scars created in their upper inner arms using skin punch biopsies. Participants were split into 4 groups; each undergoing different modes of application versus placebo: Group 1=priming (7D) pre-injury, Group 2=priming (3D) pre-injury, Group 3=immediate (0D) day-of-injury, Group 4=delayed application (14D) post-injury. RNA sequencing was used here based on 72 samples: Group 1: day 0 (n=3 placebo, n=3 EGCG), week 4 (n=3 placebo, n=3 EGCG), week 8 (n=3 placebo, n=3 EGCG); Group 2: day 0 (n=3 placebo, n=3 EGCG), week 4 (n=3 placebo, n=3 EGCG), week 8 (n=3 placebo, n=3 EGCG), Group 3: day 0 (n=6), week 4 (n=3 placebo, n=3 EGCG), week 8 (n=3 placebo, n=3 EGCG), Group 4: day 0 (n=6), week 4 (n=3 placebo, n=3 EGCG), week 8 (n=3 placebo, n=3 EGCG). The common differentially expressed genes identified between treated (EGCG) and placebo samples were grouped according to time point and group. Further exploration of these genes using Gene Ontology and Ingenuity Pathway Analysis revealed gene signatures of relevant biological processes and pathways. Here, RNA sequencing revealed a number of angiogenic, inflammatory genes that were significantly downregulated with EGCG particularly in pre-emptive priming Group 1 at week 4 including; hemoglobin subunit beta (HBB), hemoglobin subunit alpha-1 (HBA1) and hemoglobin subunit alpha-2 (HBA2) at week-4.

2020-12-01 | GSE152781 | GEO

Suppression of LPS-induced transcription and cytokine secretion by the dietary isothiocyanate sulforaphane

Project description:Consumption of a diet rich in cruciferous vegetables is associated with decreased risk of developing non-communicable chronic disease. It has been proposed that biologically active isothiocyanates (ITCs) obtained from these vegetables, such as sulforaphane (SF) derived from broccoli, are responsible for mediating health benefits via multiple mechanisms of action. ITCs have been shown to suppress the levels of several LPS-induced pro-inflammatory cytokines that are biomarkers for chronic inflammatory conditions, and which have been associated with the development of both cancer and cardiovascular disease. In patients suffering from chronic inflammatory diseases, LPS is elevated in circulation to levels reaching around 1ng/ml. In the current study, we demonstrate that SF suppresses global changes in gene expression induced by LPS exposure (1ng/ml) in human THP-1 cells at a physiologically achievable concentration of 5 micromolar. These results illustrate the profound effect that SF can have at concentrations achievable through the consumption of broccoli in suppressing TLR4-mediated inflammatory pathways.

2014-12-03 | E-MEXP-3931 | biostudies-arrayexpress

A novel treatment for glioblastoma based on Taxol activation of PC1/3-depleted macrophages: evidence from a proteomic and functional study.

Project description:Tumor-associated macrophages contribute to tumor pathogenesis and represent an attractive therapeutic target. We report that the proprotein convertase PC1/3 inhibits the TLR4 Myd88-pathway induced in macrophages by the anti-cancer agent Taxol. Thus, PC1/3 knock-down in these cells exacerbates the TLR4 MyD88-dependent pathway triggered by Taxol. In PC1/3 knock-down macrophages, Taxol drives the secretion of pro-inflammatory cytokines, inhibits STAT3 signaling and counteracts tumor-supportive activities, thus inhibiting viability, growth and invasion of glioblastoma cells. Proteomic analyses indicate that their secretomes are characterized by a unique protein profile supporting a specific paracrine anti-tumoral effect. These findings unravel the potential value of a new therapeutic strategy combining PC1/3 inhibition and activation of the TLR4 MyD88-dependent pathway to switch intra-tumoral macrophages toward an anti-tumoral immunophenotype.

2018-03-19 | PXD004444 | Pride

Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin

Project description:Inhibition of Janus kinase (JAK) family enzymes has surged as a popular strategy for treating inflammatory and autoimmune skin diseases. In the clinic, current available small molecule JAK inhibitors show distinct efficacy and safety profiles, likely reflecting their variable selectivity for JAK subtypes. Nonselective inhibition of multiple JAK enzymes is associated with increased side effects and has resulted in FDA-mandated black box warnings. Developing therapeutics to enable absolute JAK subtype selectivity is challenging and has not yet been achieved. Here, we harness RNA interference (RNAi) for rationally designing small interfering RNA (siRNA) therapeutics that offer sequence-specific gene silencing of JAK1, thus narrowing the spectrum of action on JAK-dependent cytokine signaling pathways to maintain efficacy and improve safety. We developed a fully chemically modified siRNA that supports efficient silencing of JAK1 expression in human skin explant and functional modulation of JAK1-dependent inflammatory signaling. A single injection of the JAK1 siRNA into mouse skin enables JAK1 silencing for 5 weeks in vivo. In a mouse model of vitiligo, local administration of the JAK1 siRNA significantly reduces skin infiltration of autoreactive CD8+ T cells and prevents epidermal depigmentation. This work outlines a robust framework for designing targeted RNAi-based therapies and establishes a path toward novel siRNA treatments for inflammatory and autoimmune skin diseases.

2023-10-18 | GSE234070 | GEO

Anti-inflammatory effects of HDL in macrophages predominate over pro-inflammatory effects in atherosclerotic plaques

Project description:HDL infusion reduces atherosclerosis in animal models and is being evaluated as a treatment in humans. While some studies have shown anti-inflammatory effects of HDL in macrophages, others have reported pro-inflammatory effects and there is no consensus on underlying mechanisms. Transcriptional profiling reveals that HDL-mediated cholesterol efflux leads to both pro- and anti-inflammatory effects in LPS-stimulated macrophages. While early anti-inflammatory effects reflect reduced TLR4 levels, late anti-inflammatory effects are due to reduced interferon receptor signaling. Pro-inflammatory effects occur late and are ER stress responses mediated by IRE1a/ASK1/p38 MAPK signaling under conditions of marked cholesterol depletion. rHDL infusions in hypercholesterolemic atherosclerotic mice produced moderate anti-inflammatory effects in lesional macrophages without pro-inflammatory gene expression changes suggesting a beneficial therapeutic effect of HDL in vivo.

2020-04-04 | GSE129347 | GEO

Disulfiram blocks inflammatory TLR4 signaling by targeting MD-2

Project description:Toll-like receptor 4 (TLR4) sensing of lipopolysaccharide (LPS), the most potent pathogen-associated molecular pattern of gram-negative bacteria, activates NF-κB and Irf3, which induces inflammatory cytokines and interferons that trigger an intense inflammatory response, which is critical for host defense but can also cause serious inflammatory pathology, including sepsis. Although TLR4 inhibition is an attractive therapeutic approach for suppressing overexuberant inflammatory signaling, previously identified TLR4 antagonists have not shown any clinical benefit. Here, we identify disulfiram (DSF), an FDA-approved drug for alcoholism, as a specific inhibitor of TLR4-mediated inflammatory signaling. TLR4 cell surface expression, LPS sensing, dimerization and signaling depend on TLR4 binding to MD-2. DSF and other cysteine-reactive drugs, previously shown to block LPS-triggered inflammatory cell death (pyroptosis), inhibit TLR4 signaling by covalently modifying Cys133 of MD-2, a key conserved residue that mediates TLR4 sensing and signaling. DSF blocks LPS-triggered inflammatory cytokine, chemokine, and interferon production by macrophages in vitro. In the aggressive N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease (PD) in which TLR4 plays an important role, DSF markedly suppresses neuroinflammation and dopaminergic neuron loss, and restores motor function. Our findings identify a role for DSF in curbing TLR4-mediated inflammation and suggest that DSF and other drugs that target MD-2 might be useful for treating PD and other diseases in which inflammation contributes importantly to pathogenesis.

2023-08-07 | GSE237028 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data