scholarly journals Monocytes Heterozygous for the Asp299Gly and Thr399Ile Mutations in the Toll-like Receptor 4 Gene Show No Deficit in Lipopolysaccharide Signalling

2003 ◽  
Vol 197 (12) ◽  
pp. 1787-1791 ◽  
Author(s):  
Clett Erridge ◽  
John Stewart ◽  
Ian R. Poxton
Keyword(s):  
High Frequency ◽  
Bacterial Infections ◽  
Physiological Responses ◽  
Italian Population ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Gram Negative ◽  
Increased Risk ◽  
Tlr4 Gene ◽  
Efficient Recognition

Toll-like receptor 4 (TLR4)-mediated recognition of lipopolysaccharide (LPS) is required for efficient recognition of Gram-negative bacterial infections. Two commonly occurring mutations in the human TLR4 gene (Asp299Gly and Thr399Ile) have recently been shown to be associated with blunted physiological responses to inhaled LPS, and with increased risk of Gram-negative bacteraemia in sepsis patients and reduced risk of atherosclerosis in an Italian population. Here we show that monocytes from individuals heterozygous for both mutations in the TLR4 gene exhibit no deficit in recognition of LPS of Escherichia coli, Neisseria meningitidis, Bacteroides fragilis, Yersinia pestis, Chlamydia trachomatis, Porphyromonas gingivalis, or Pseudomonas aeruginosa. We propose that the relatively high frequency of these mutations in the Caucasian population may reflect modified responses of carriers to alternative TLR4 agonists.

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 Overexpression of Toll-like receptor 4 contributes to the internalization and elimination of Escherichia coli in sheep by enhancing caveolae-dependent endocytosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yao Li ◽  
Yue Zhao ◽  
Xueling Xu ◽  
Rui Zhang ◽  
Jinlong Zhang ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Animal Model ◽  
Disease Resistance ◽  
Bacterial Infections ◽  
Toll Like Receptor ◽  
Defence Mechanism ◽  
Toll Like Receptor 4 ◽  
Gram Negative ◽  
Transgenic Sheep ◽  
Endocytosis Pathway

Abstract Background Gram-negative bacterial infections have a major economic impact on both the livestock industry and public health. Toll-like receptor 4 (TLR4) plays a crucial role in host defence against Gram-negative bacteria. Exploring the defence mechanism regulated by TLR4 may provide new targets for treatment of inflammation and control of bacterial infections. In a previous study, we generated transgenic sheep overexpressing TLR4 by microinjection to improve disease resistance. The defence mechanism through which TLR4 overexpression protected these sheep against pathogens is still not fully understood. Results In the present study, we used Escherichia coli to infect monocytes isolated from peripheral blood of the animal model. The overexpression of TLR4 strongly enhanced the percentage of endocytosis and capacity of elimination in monocytes during the early stages of infection. This phenomenon was mainly due to overexpression of TLR4 promoting caveolae-mediated endocytosis. Pretreatment of the transgenic sheep monocytes with inhibitors of TLR4, Src signalling, or the caveolae-mediated endocytosis pathway reduced the internalization of bacteria, weakened the ability of the monocytes to eliminate the bacteria, and increased the pH of the endosomes. Conclusion Together, our results reveal the effects of TLR4 on the control of E. coli infection in the innate immunity of sheep and provide crucial evidence of the caveolae-mediated endocytosis pathway required for host resistance to invading bacteria in a large animal model, providing theoretical support for breeding disease resistance in the future. Furthermore, Src and caveolin 1 (CAV1) could be potentially valuable targets for the control of infectious diseases.

Toll-Like Receptor 4 Polymorphisms and the Risk of Gram-Negative Bacterial Infections After Liver Transplantation

2011 ◽  
Vol 92 (6) ◽  
pp. 690-696 ◽  
Author(s):  
Sang-Oh Lee ◽  
Robert A. Brown ◽  
Seung H. Kang ◽  
Rima C. Abdel Massih ◽  
Raymund R. Razonable
Keyword(s):  
Liver Transplantation ◽  
Bacterial Infections ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Gram Negative

Toll-Like Receptor 4 Polymorphisms in Gram-Negative Bacterial Infections of Han Chinese Neonates

2014 ◽  
Vol 32 (04) ◽  
pp. 363-370 ◽  
Author(s):  
Ben Lee ◽  
Shu-Lian Zhang ◽  
Li Zhu ◽  
Jian-Guo Zhou ◽  
Jin-Ping Zhang ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Han Chinese ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Gram Negative

scholarly journals Human Toll‐Like Receptor 4 Mutations but Not CD14 Polymorphisms Are Associated with an Increased Risk of Gram‐Negative Infections

2002 ◽  
Vol 186 (10) ◽  
pp. 1522-1525 ◽  
Author(s):  
Doreen M. Agnese ◽  
Jacqueline E. Calvano ◽  
Sae J. Hahm ◽  
Susette M. Coyle ◽  
Siobhan A. Corbett ◽  
...  
Keyword(s):  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Gram Negative ◽  
Increased Risk

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

scholarly journals Effect of Spaceflight on Ability of Monocytes To Respond to Endotoxins of Gram-Negative Bacteria

2008 ◽  
Vol 15 (10) ◽  
pp. 1523-1528 ◽  
Author(s):  
Indreshpal Kaur ◽  
Elizabeth R. Simons ◽  
Asha S. Kapadia ◽  
C. Mark Ott ◽  
Duane L. Pierson
Keyword(s):  
Space Shuttle ◽  
Space Station ◽  
Gram Negative Bacteria ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Gram Negative ◽  
Time Points ◽  
Control Subjects ◽  
Intracellular Cytokines ◽  
Blood Specimens

ABSTRACT Astronauts live and work in relatively crowded, confined environments on the Space Shuttle and the International Space Station. They experience a unique set of stressors that contribute to a diminishment of many immune responses. This study investigated the ability of the shuttle crew members' monocytes to respond to gram-negative endotoxin that they could encounter during infections. Blood specimens were collected from 20 crew members and 15 control subjects 10 days before launch, 3 to 4 h after landing, and 15 days after landing and from crew members during their annual medical examination at 6 to 12 months after landing. When challenged with gram-negative endotoxin, the crew member's monocytes collected at all three time points produced lower levels of interleukin-6 (IL-6) and IL-1β and higher levels of IL-1ra and IL-8 compared to those of control subjects. Cytokines were assessed by measuring the number of cells positive for intracellular cytokines. These values returned to normal 6 to 12 months after landing, except for IL-1ra, which was still higher (five- to sixfold) than in controls. This phenomenon was accompanied by an increased expression of Toll-like receptor 4 and decreased expression of CD14 on the crew members' monocytes at all time points. There were also increased levels of the lipopolysaccharide binding protein in the plasma of the crew members 3 to 4 h and 15 days after landing. This study shows that spaceflight-associated factors (in-flight and preflight) modulate the response of monocytes to gram-negative endotoxins.

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