Association between functional polymorphisms in the toll-like receptor 4 (TLR4) gene and HD severity

2015 ◽  
Vol 85 (3) ◽  
pp. 209-211 ◽  
Author(s):  
N. Inoue ◽  
M. Watanabe ◽  
Y. Katsumata ◽  
N. Ishido ◽  
Y. Hidaka ◽  
...  
Keyword(s):  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Functional Polymorphisms ◽  
Tlr4 Gene

A896G and C1196T Polymorphisms Within the TLR4 Gene Abate Toll-Like Receptor 4-Mediated Signaling in HepG2 Cells

2017 ◽  
Vol 36 (11) ◽  
pp. 1029-1038 ◽  
Author(s):  
Cuiyuan Huang ◽  
Hong Zhang ◽  
Ruidan Bai ◽  
Li Wang ◽  
Jian Lv
Keyword(s):  
Hepg2 Cells ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Tlr4 Gene

Abstract 2874: Functional Polymorphisms in Toll-like Receptor 4 Predict Worse Outcome in Acute Ischemic Stroke Patients

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Jonathan R Weinstein ◽  
Juliane Schulze ◽  
Richard V Lee ◽  
Dannielle Zierath ◽  
Patricia Tanzi ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Immune Cell ◽  
Stroke Severity ◽  
Multiple Time ◽  
Toll Like Receptor ◽  
C Reactive Protein ◽  
Toll Like Receptor 4 ◽  
Reactive Protein ◽  
Functional Polymorphisms

Background: Toll-like receptor-4 (TLR4) plays a central role in the pathophysiology of acute ischemic stroke (AIS). Specific single nucleotide polymorphisms (SNPs) in TLR4 including 1063 A/G [Asp299Gly] and 1363 C/T [Thr399Ile] alter immune cell responsiveness to lipopolysaccharide (LPS) and are associated with increased rates of infection. The effect of these TLR4 SNPs on outcome following AIS is unknown. Methods: Patients were prospectively enrolled after onset of AIS. Clinical and demographic data were collected and neurological outcomes assessed at 3 months. Blood was drawn at multiple time points to quantify leukocyte subsets and assess plasma levels of C-reactive protein and a panel of cytokines. Genotyping for the TLR4 SNPs was also performed on blood samples. Uni- and multivariate analyses were performed to assess associations between TLR4 SNP haplotype and (i) each laboratory parameter noted above, (ii) infection risk and (iii) stroke outcome. Results: Of the 42 patients included; 6 (14%) were heterozygous for either one or both TLR4 SNPs. Baseline characteristics were similar in patients with or without a TLR4 SNP. In analyses adjusted for both initial stroke severity and age, the presence of a TLR4 SNP was associated with increases in blood leukocytes, plasma C-reactive protein and the cytokine interleukin-1 receptor antagonist (IL-1ra). The presence of either TLR4 SNP was also associated with a trend toward increased rates of infection (adjusted odds ratio and 95% confidence interval of 8.20 and 0.826-81.5, respectively) and a decreased likelihood of favorable outcome as defined by a modified Rankin Scale score of two or less at three months from stroke onset (0.014, 0.00-0.759). Conclusions: In AIS patients, functionally significant genetic variations in TLR4 influence both rates of stroke-associated infection and neurological outcome. These data suggest a direct connection between TLR4 function and stroke pathophysiology.

scholarly journals Critical role for Ets, AP-1 and GATA-like transcription factors in regulating mouse Toll-like receptor 4 (Tlr4) gene expression

2005 ◽  
Vol 387 (2) ◽  
pp. 355-365 ◽  
Author(s):  
Thierry ROGER ◽  
Isabelle MICONNET ◽  
Anne-Laure SCHIESSER ◽  
Hirofumi KAI ◽  
Kensuke MIYAKE ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Promoter Activity ◽  
Critical Role ◽  
Regulatory Elements ◽  
Mrna Levels ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Gram Negative ◽  
Inflammatory Stimuli ◽  
Tlr4 Gene

TLR4 (Toll-like receptor 4) is essential for sensing the endotoxin of Gram-negative bacteria. Mutations or deletion of the TLR4 gene in humans or mice have been associated with altered predisposition to or outcome of Gram-negative sepsis. In the present work, we studied the expression and regulation of the Tlr4 gene of mouse. In vivo, TLR4 levels were higher in macrophages compared with B, T or natural killer cells. High basal TLR4 promoter activity was observed in RAW 264.7, J774 and P388D1 macrophages transfected with a TLR4 promoter reporter vector. Analysis of truncated and mutated promoter constructs identified several positive [two Ets (E twenty-six) and one AP-1 (activator protein-1) sites] and negative (a GATA-like site and an octamer site) regulatory elements within 350 bp upstream of the transcriptional start site. The myeloid and B-cell-specific transcription factor PU.1 bound to the proximal Ets site. In contrast, none among PU.1, Ets-1, Ets-2 and Elk-1, but possibly one member of the ESE (epithelium-specific Ets) subfamily of Ets transcription factors, bound to the distal Ets site, which was indispensable for Tlr4 gene transcription. Endotoxin did not affect macrophage TLR4 promoter activity, but it decreased TLR4 steady-state mRNA levels by increasing the turnover of TLR4 transcripts. TLR4 expression was modestly altered by other pro- and anti-inflammatory stimuli, except for PMA plus ionomycin which strongly increased promoter activity and TLR4 mRNA levels. The mouse and human TLR4 genes were highly conserved. Yet, notable differences exist with respect to the elements implicated in gene regulation, which may account for species differences in terms of tissue expression and modulation by microbial and inflammatory stimuli.

scholarly journals Trichinella spiralis: impact on the expression of Toll-like receptor 4 (TLR4) gene during the intestinal phase of experimental trichinellosis

2018 ◽  
Vol 62 (4) ◽  
pp. 493-496
Author(s):  
Agnieszka Wojtkowiak-Giera ◽  
Elżbieta Wandurska-Nowak ◽  
Monika Derda ◽  
Wiesława Jankowska ◽  
Paweł P. Jagodziński ◽  
...  
Keyword(s):  
Immune Response ◽  
Trichinella Spiralis ◽  
Mrna Level ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Intestinal Phase ◽  
Strong Positive Reaction ◽  
Tlr4 Gene ◽  
Rapid Activation

AbstractIntroduction: Toll-like receptors (TLRs) play a key role in the rapid activation of the innate immune response to a variety of pathogens. The aim of this study was to evaluate the effect of Trichinella spiralis infection on the level of expression of the tlr4 gene in mouse intestines during the intestinal phase of experimental trichinellosis.Material and Methods: The experimental material consisted of the small and large intestines of BALB/c mice infected with Trichinella spiralis sampled at 4, 8, and 16 days post infection (dpi).Results: A statistically significant increase was demonstrated in the tlr4 mRNA level isolated from the infected mice jejunum at 4, 8, and 16 dpi over the uninfected control. Moreover, at 4, 8, and 16 dpi in the jejunum of infected mice, a strong positive reaction for the presence of TLR4 protein compared with that of uninfected mice was observed.Conclusion: Infection with T. spiralis changes the expression of the tlr4 gene in the small intestine of the mouse host.

In vivo effects of lipopolysaccharide and TLR4 on platelet production and activity: implications for thrombotic risk

2007 ◽  
Vol 102 (1) ◽  
pp. 429-433 ◽  
Author(s):  
Muthuvel Jayachandran ◽  
Gregory J. Brunn ◽  
Krzysztof Karnicki ◽  
Randall S. Miller ◽  
Whyte G. Owen ◽  
...  
Keyword(s):  
Gram Negative Bacteria ◽  
Toll Like Receptor ◽  
Single Exposure ◽  
Toll Like Receptor 4 ◽  
Thrombotic Risk ◽  
Atp Secretion ◽  
Tlr4 Gene ◽  
Risk For Thrombosis ◽  
In Vivo Effects

Gram-negative bacteria release LPS, which activates Toll-like-receptor-4 (TLR4) in the host, initiating an inflammatory response to infection. Infection increases risk for thrombosis. Platelets contribute to defense from infection and to thrombosis. Experiments were designed to determine whether LPS, through TLR4 signaling, affects platelet phenotype. Platelet responses in wild-type (WT) mice and mice that lack the TLR4 gene (dTLR4) were compared following a single nonlethal injection of LPS (0.2 mg/kg iv). Compared with WT mice, mice without TLR4 had fewer circulating platelets with lower RNA content and were less responsive to thrombin-activated expression of P-selectin but were equally sensitive to aggregation or ATP secretion. One week following the LPS injection, the time it takes for the circulating platelet pool to turnover, the number of circulating platelets, thrombin-induced expression of P-selectin, and collagen-activated aggregation were increased comparably in both groups of mice. Therefore, the change of the platelet pool to an activated phenotype 1 wk after a single exposure to LPS appears to arise from a process that is independent of TLR4. The persistence of the effect 1 wk after the injection suggests that the changes reflect an action of LPS on megakaryocytes and their platelet progeny rather than on circulating platelets, which would have been cleared.

scholarly journals Functional polymorphisms in toll-like receptor 4 are associated with worse outcome in acute ischemic stroke patients

Neuroreport ◽  
2014 ◽  
pp. 1 ◽  
Author(s):  
Jonathan R. Weinstein ◽  
Juliane Schulze ◽  
Richard V. Lee ◽  
Hunter Phillips ◽  
Dannielle Zierath ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Toll Like Receptor ◽  
Stroke Patients ◽  
Toll Like Receptor 4 ◽  
Functional Polymorphisms

Inducible binding of PU.1 and interacting proteins to the Toll-like receptor 4 promoter during endotoxemia

2005 ◽  
Vol 289 (3) ◽  
pp. L429-L437 ◽  
Author(s):  
Tetyana V. Pedchenko ◽  
Gye Young Park ◽  
Myungsoo Joo ◽  
Timothy S. Blackwell ◽  
John W. Christman
Keyword(s):  
Gene Expression ◽  
Lung Tissue ◽  
Raw 264.7 Cells ◽  
Dependent Manner ◽  
Interacting Proteins ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Tlr4 Mrna ◽  
Tlr4 Gene

We hypothesized that PU.1 and PU.1 interacting proteins (PIP) binding to the Toll-like receptor 4 (TLR4) promoter is involved in endotoxin-induced upregulation of TLR4 gene expression. Our results employing chromatin immunoprecipitation assays indicate that PU.1 binds to the murine TLR4 promoter both in macrophage cells and, most importantly, in whole lung tissue. Treatment of RAW 264.7 cells with endotoxin induced the association of PU.1 and the TLR4 promoter in a time-dependent manner, and this was closely tied to interactions between the TLR4 promoter and the PIP interferon regulatory factors (IRF)4 and IRF8. PU.1 binding was related to increases in steady-state TLR4 mRNA and total TLR4 protein in RAW cells. Endotoxemia in animals caused the similar inducible interaction between PU.1 and IRF4 and the TLR4 promoter in lung tissue of mice that was treated with a single intraperitoneal injection of endotoxin. PU.1 binding to the TLR4 promoter was not enhanced in the lung tissue of endotoxin-resistant C3H/HeJ mice in response to endotoxemia. Transient transfection studies in RAW cells indicate that inducible binding of PU.1 to the TLR4 promoter is abrogated by a Ser148 to Ala mutation in PU.1. These data suggest that induction of PU.1/PIP binding to the TLR4 promoter is involved in endotoxin response in vivo and may mediate transcriptional changes in TLR4 gene expression.

scholarly journals Toll-like receptor 4 signaling activates ERG function in prostate cancer and provides a therapeutic target

NAR Cancer ◽  
2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Benjamin M Greulich ◽  
Joshua P Plotnik ◽  
Travis J Jerde ◽  
Peter C Hollenhorst
Keyword(s):  
Prostate Cancer ◽  
Transcription Factor ◽  
Transcriptional Activation ◽  
Gene Activation ◽  
Clonogenic Survival ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Critical Function ◽  
Tlr4 Signaling ◽  
Tlr4 Gene

Abstract The TMPRSS2–ERG gene fusion and subsequent overexpression of the ERG transcription factor occurs in ∼50% of prostate tumors, making it the most common abnormality of the prostate cancer genome. While ERG has been shown to drive tumor progression and cancer-related phenotypes, as a transcription factor it is difficult to target therapeutically. Using a genetic screen, we identified the toll-like receptor 4 (TLR4) signaling pathway as important for ERG function in prostate cells. Our data confirm previous reports that ERG can transcriptionally activate TLR4 gene expression; however, using a constitutively active ERG mutant, we demonstrate that the critical function of TLR4 signaling is upstream, promoting ERG phosphorylation at serine 96 and ERG transcriptional activation. The TLR4 inhibitor, TAK-242, attenuated ERG-mediated migration, clonogenic survival, target gene activation and tumor growth. Together these data indicate a mechanistic basis for inhibition of TLR4 signaling as a treatment for ERG-positive prostate cancer.

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