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.

Functional Toll-like receptor 4 mutations modulate the response to fibrinogen

2008 ◽  
Vol 100 (08) ◽  
pp. 301-307 ◽  
Author(s):  
Kunal Patel ◽  
Shu Ye ◽  
Conrad P. Hodgkinson
Keyword(s):  
Transcription Factors ◽  
Promoter Activity ◽  
Activator Protein 1 ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Human Macrophages ◽  
Inflammatory Protein ◽  
Extracellular Signal ◽  
Cytokine Synthesis ◽  
Kinase Phosphorylation

SummaryFibrinogen has been implicated in atherosclerosis; in part by activating the lipopolysaccharide (LPS) receptor Toll-like receptor 4 (TLR4). The fibrinogen-TLR4 signalling pathway remains un-characterised. In human macrophages fibrinogen stimulated interleukin (IL)6 expression and ERK (extracellular signal-related kinase) phosphorylation. In HEK293-CD14-MD2 cells expressing TLR4, fibrinogen induced robust phosphorylation of ERK1, p38α and JNK and activated transcription factors NFκB, Elk-1 and AP-1 (activator protein-1).The net effect of this signaling pathway was a pro-inflammatory response characterised by IL6 and TNFα synthesis and increased IL8,matrix metalloproteinase (MMP)1, MMP9, and MCP-1 promoter activity. Two common TLR4 mutations, D299G and T399I, render the receptor LPS hyporesponsive. The effect of fibrinogen on polymorphic variant TLR4s was markedly different; enhancing activation of kinases, transcription factors, cytokine synthesis and promoter activity. This study indicates that fibrinogen activates TLR4, explaining how fibrinogen promotes inflammatory protein expression.

scholarly journals Induction of TNF-α and MnSOD by endotoxin: role of membrane CD14 and Toll-like receptor-4

2001 ◽  
Vol 280 (6) ◽  
pp. C1422-C1430 ◽  
Author(s):  
Min-Fu Tsan ◽  
Robert N. Clark ◽  
Sanna M. Goyert ◽  
Julie E. White
Keyword(s):  
Manganese Superoxide Dismutase ◽  
Nuclear Factor Κb ◽  
Peritoneal Macrophages ◽  
Mrna Levels ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Potent Inducer ◽  
Tnf Α ◽  
Tlr4 Gene

Endotoxin (LPS) is a potent inducer of tumor necrosis factor-α (TNF-α) and manganese superoxide dismutase (MnSOD). Recent evidence suggests that LPS induction of TNF-α and MnSOD mRNAs is mediated through distinct intracellular signal transduction pathways. Membrane CD14 (mCD14) and Toll-like receptor-4 (TLR4) mediate LPS induction of TNF-α in macrophages. In the current study, we evaluated the role of mCD14 and TLR4 in LPS induction of MnSOD using peritoneal macrophages from CD14 knockout (CD14-KO) mice and mice with the Tlr4 gene point mutation (C3H/HeJ) or deletion (C57BL/10ScCr). We studied mCD14-dependent (1 and 10 ng/ml) and mCD14-independent (1,000 ng/ml) concentrations of LPS. Compared with control (BALB/c) macrophages, LPS at 1 and 10 ng/ml failed to induce TNF-α or MnSOD mRNA in CD14-KO macrophages. However, LPS at 1,000 ng/ml induced TNF-α and MnSOD mRNAs equally in macrophages from CD14-KO and control mice. LPS (1, 10, or 1,000 ng/ml) failed to induce TNF-α or MnSOD mRNA and failed to activate nuclear factor-κB in C3H/HeJ or C57BL/10ScCr macrophages. Measurements of TNF-α and MnSOD enzyme activity paralleled TNF-α and MnSOD mRNA levels. These data demonstrate that, like TNF-α, induction of MnSOD by LPS is mediated by mCD14 and TLR4 in murine macrophages.

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.

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

Oxymatrine inhibits lipopolysaccharide-induced inflammation by down-regulating Toll-like receptor 4/nuclear factor-kappa B in macrophages

2015 ◽  
Vol 93 (4) ◽  
pp. 253-260 ◽  
Author(s):  
Yu Zhang ◽  
Ruhong Yan ◽  
Yae Hu
Keyword(s):  
Nitric Oxide ◽  
Interleukin 1 ◽  
Chinese Herb ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Anti Inflammatory

Oxymatrine (OMT) is the quinolizidine alkaloid extracted from the Chinese herb Sophora flavescens Ait. that has many pharmacological effects and is used for the treatment of some inflammatory diseases. In this study, RAW264.7 cells and THP-1 differentiated macrophages were pretreated with various concentrations of OMT at 2 h prior to treatment with lipopolysaccharide (LPS) (1.0 μg/mL) for different durations. We detected the anti-inflammatory effect of OMT in LPS-stimulated macrophages and investigated the molecular mechanism. We showed that OMT pretreatment significantly inhibited the LPS-induced secretion of nitric oxide (NO), interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) in supernatant, attenuated the mRNA levels of inducible nitric oxide synthase (iNOS), IL-1β, TNF-α, and Toll-like receptor 4 (TLR4), increased TLR4 and phosphorylation of inhibitor of kappa B-alpha (p-IBα) in cytosol, and decreased the nuclear level of nuclear factor-κB (NF-κB) p65 in macrophages. In conclusion, OMT exerts anti-inflammatory properties in LPS-stimulated macrophages by down-regulating the TLR4/NF-κB pathway.

Critical role of toll-like receptor 4 (TLR4) in dextran sulfate sodium (DSS)-Induced intestinal injury and repair

2019 ◽  
Vol 315 ◽  
pp. 23-30 ◽  
Author(s):  
Yun-Jie Shi ◽  
Hai-Feng Gong ◽  
Quan-Quan Zhao ◽  
Xiao-Shuang Liu ◽  
Cong Liu ◽  
...  
Keyword(s):  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Critical Role ◽  
Intestinal Injury ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Injury And Repair

scholarly journals Human resistin protects against endotoxic shock by blocking LPS–TLR4 interaction

2017 ◽  
Vol 114 (48) ◽  
pp. E10399-E10408 ◽  
Author(s):  
Jessica C. Jang ◽  
Jiang Li ◽  
Luca Gambini ◽  
Hashini M. Batugedara ◽  
Sandeep Sati ◽  
...  
Keyword(s):  
Immune Cell ◽  
Inflammatory Responses ◽  
Endotoxic Shock ◽  
Critical Role ◽  
Nippostrongylus Brasiliensis ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Therapeutic Function ◽  
Human Immune ◽  
Human Resistin

Helminths trigger multiple immunomodulatory pathways that can protect from sepsis. Human resistin (hRetn) is an immune cell-derived protein that is highly elevated in helminth infection and sepsis. However, the function of hRetn in sepsis, or whether hRetn influences helminth protection against sepsis, is unknown. Employing hRetn-expressing transgenic mice (hRETNTg+) and recombinant hRetn, we identify a therapeutic function for hRetn in lipopolysaccharide (LPS)-induced septic shock. hRetn promoted helminth-induced immunomodulation, with increased survival of Nippostrongylus brasiliensis (Nb)-infected hRETNTg+ mice after a fatal LPS dose compared with naive mice or Nb-infected hRETNTg− mice. Employing immunoprecipitation assays, hRETNTg+Tlr4−/− mice, and human immune cell culture, we demonstrate that hRetn binds the LPS receptor Toll-like receptor 4 (TLR4) through its N terminal and modulates STAT3 and TBK1 signaling, triggering a switch from proinflammatory to anti-inflammatory responses. Further, we generate hRetn N-terminal peptides that are able to block LPS proinflammatory function. Together, our studies identify a critical role for hRetn in blocking LPS function with important clinical significance in helminth-induced immunomodulation and sepsis.

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