Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Toll-like receptor (TLR) molecules play a frontline role in the defence of the host against infection by microbial pathogens. These molecules, together with the recently described Nod family proteins, have been shown to trigger innate immune responses in host cells via the recognition of highly conserved microbial structures. TLR4, which is the best-characterised of these "pathogen-recognition molecules" (PRMs), was the first to be shown to recognise a specific microbial component: the lipopolysaccharide (LPS) from Gram-negative bacteria. The molecular specificities of the remaining PRMs have, in nearly all cases, now also been elucidated. Host cells belonging to the myeloid cell lineage are known to be particularly responsive to these microbial constituents. Conversely, other cell types such as epithelial cells, were generally thought to be hypo-responsive to stimulation by such molecules. New evidence suggests that these cells are in fact likely to play a fundamental role in host defence against pathogenic micro-organisms. Indeed, epithelial cells afford an initial barrier against the host microflora, and appear to be able to differentiate between pathogenic and commensal micro-organisms. This review article will discuss current knowledge regarding innate immune responses in epithelial and myeloid cells to the model non-invasive pathogen, Helicobacter pylori, which is a major cause of upper gastrointestinal tract disease in humans.
Mol Immunol 2005 May
PMID:Innate immune recognition of the extracellular mucosal pathogen, Helicobacter pylori. 1582 77

The innate immune system recognises a wide spectrum of pathogens without a need for prior exposure. The main cells responsible are monocytes, macrophages, dendritic cells (DC) and neutrophils phagocytose microbial pathogens triggering a cytokine network resulting in the development of inflammatory and specific immune responses. Findings in the Toll-like receptor (TLR) family, initially discovered in Drosophila, further elucidated these processes. Toll-like receptors induce activation of an innate immune response and at present ten TLRs have been identified, named TLRs 1-10. In addition to the ignition of the innate immune response, evidence implicates the TLR family in a spectrum of systemic disorders following bacterial infections including sepsis and multiple organ failure, and can be detrimental, leading to tissue injury. In this project, our main goal was to investigate the effects of a TLR4 ligand, lipolysaccharide (LPS) in human DC and monocytes. Our hypothesis is that different professional APCs, express different mRNA TLR transcripts. Our findings indicate that TLR expression patterns change in relation to the pathogen involved and in the case of DC, and the maturation stage the latter are upon challenging. Our results and interpretation showed significant alteration of transcript expression patterns upon LPS challenge in all cell subsets, with DC subsets expressing different TLR mRNA patterns as they go through different maturation stages.
Mol Immunol 2005 May
PMID:Toll-like receptor mRNA expression patterns in human dendritic cells and monocytes. 1582 87

Numerous microbial as well as other stimulants including lipopolysaccharide and taxol can activate TLR4, and elicit diverse downstream signaling events including cytokine gene expression and cell growth regulation. With a mechanism not completely understood, different TLR4 stimulants induce distinct cellular responses. Our present studies showed that taxol, not LPS, induced cell apoptosis in human monocytic THP-1 cells, as indicated by PARP cleavage, as well as bcl-2 phosphorylation. Pretreatment of cells with LPS abolished subsequent taxol effect, suggesting that certain signaling components involved in taxol-mediated apoptosis were disrupted by LPS pretreatment. Since the decrease in IRAK-1 level closely accompanies prolonged LPS treatment in monocytic cells, we investigated the IRAK-1 status upon various taxol and LPS challenges. We observed that only LPS, not taxol, caused dramatic decrease in IRAK-1 protein levels. Using splenic macrophages harvested from IRAK-1 knockout and control mice, we further demonstrated that the presence of IRAK-1 is required for taxol-induced PARP cleavage.
Mol Immunol 2005 May
PMID:Differential induction of apoptosis by LPS and taxol in monocytic cells. 1582 95

Age-related macular degeneration (AMD) is a genetically heterogeneous disease that leads to progressive and irreversible vision loss among the elderly. Inflammation, oxidative damage, cholesterol metabolism and/or impaired function of retinal pigment epithelium (RPE) have been implicated in AMD pathogenesis. We examined toll-like receptor 4 (TLR4) as a candidate gene for AMD susceptibility because: (i) the TLR4 gene is located on chromosome 9q32-33, a region exhibiting evidence of linkage to AMD in three independent reports; (ii) the TLR4-D299G variant is associated with reduced risk of atherosclerosis, a chronic inflammatory disease with subendothelial accumulation; (iii) the TLR4 is not only a key mediator of proinflammatory signaling pathways but also linked to regulation of cholesterol efflux and (iv) the TLR4 participates in phagocytosis of photoreceptor outer segments by the RPE. We examined D299G and T399I variants of TLR4 in a sample of 667 unrelated AMD patients and 439 unrelated controls, all of Caucasian ancestry. Multiple logistic regression demonstrated an increased risk of AMD in carriers of the G allele at TLR4 residue 299 (odds ratio=2.65, P=0.025), but lack of an independent effect by T399I variant. TLR4-D299G showed an additive effect on AMD risk (odds ratio=4.13, P=0.002) with allelic variants of apolipoprotein E (APOE) and ATP-binding cassette transporter-1 (ABCA1), two genes involved in cholesterol efflux. Interestingly, the effect of TLR4, APOE and ABCA1 variants on AMD susceptibility was opposite to that of association with atherosclerosis risk. Our data provide evidence of a link between multiple diverse mechanisms underlying AMD pathogenesis.
Hum Mol Genet 2005 Jun 01
PMID:Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration. 1582 98

Although chronic inhalation of endotoxin or lipopolysaccharide (LPS) causes all of the classic features of asthma, including airway hyperreactivity, airway inflammation, and airway remodeling, the mechanisms involved in this process are not clearly understood. The objective of this study was to determine whether intratracheal treatment with LPS antagonist (E5564, a lipid A analog) prevented the development of chronic endotoxin-induced airway disease in a mouse model of environmental airway disease. Pretreatment with 10 and 100 microg of E5564 was found to inhibit the airway response (hyperreactivity and inflammation) for up to 48 h after the administration of the compound. Repeated dosing with 50 microg of E5564 intratracheally did not cause any measurable toxicity. Therefore, in a chronic experiment, mice were treated with either E5564 (50 microg) or vehicle three times weekly for 5 wk and simultaneously daily exposed to either LPS (4.65 +/- 0.30 microg/m3) or saline aerosol. E5564 was effective in decreasing the airway hyperreactivity to methacholine, the air space neutrophilia, the interleukin-6 in the lung lavage fluid, and the neutrophil infiltration of the airways 36 h after 5 wk of LPS inhalation. Less collagen deposition was observed in the airways of E5564-treated mice compared with vehicle-treated mice after a 4-wk recovery period. Our results indicate that E5564, a Toll-like receptor 4 antagonist, minimizes the physiological and biological effects of chronic LPS inhalation, suggesting a therapeutic role for competitive LPS antagonists in preventing or reducing endotoxin-induced environmental airway disease.
Am J Physiol Lung Cell Mol Physiol 2005 Aug
PMID:Toll-like receptor 4 antagonist (E5564) prevents the chronic airway response to inhaled lipopolysaccharide. 1583 64

Toll-like receptor 4 (TLR4) is essential for initiating the innate response to lipopolysaccharide (LPS) from Gram-negative bacteria by acting as a signal-transducing receptor. As the pig industry faces a unique array of related pathogens, it is anticipated that the genotype of swine TLR4 could be of crucial importance in future strategies aimed at improving genetic resistance to infectious diseases. In order to help in investigating TLR4 as a candidate disease-resistance gene in pigs, we established its genomic structure and produced sufficient flanking intronic sequences to enable simple PCR amplification of the coding portions of the gene. Expression in different porcine tissues was studied and showed splicing variations in mRNA sequences. The cDNA sequence for poTLR4 contains an open reading frame of 2526bp that codes for 841 aa, 98 and 568bp in the 5'- and 3'-UTRs, respectively. Overall, the general organization of porcine, human, murine, and avian TLR4 genes is quite similar: three exons with the third one very long. A high level of conservation of the size and the sequence, especially for the two last exons and particularly in the sequence corresponding to the LRRs and TIR domain, is observed between species. The important antimicrobial properties of these proteins may account for a conservative selection pressure on these TLR4 coding sequences. Several putative binding sites described in the human and murine promoter of TLR4 genes have been identified in the 5'-flanking region of poTLR4. Conversely, this region lacks a TATA box, consensus initiator sequences, or GC-rich regions. The basic sequence data gathered will allow the establishment of an inventory of naturally occurring variation in porcine TLR4, so that alleles can be tested for disease association studies.
Mol Immunol 2006 Feb
PMID:Genomic structure, promoter analysis and expression of the porcine (Sus scrofa) TLR4 gene. 1586 93

Restenosis is a major problem for patients undergoing percutaneous transluminal coronary angioplasty (PTCA). Inflammatory processes and genetic factors have been suggested to be involved in the pathogenesis of both atherosclerosis and restenosis. The recently discovered family of Toll-like receptors (TLRs) consists of molecules that initiate signaling after host-pathogen interactions. Recently it has been shown that the TLRs are involved in the development and progression of atherosclerosis by interfering with lipid metabolisms and by mediating inflammation. TLR-2 is a key innate immunity receptor for sensing both endogenous inflammatory mediators and ligands of several microbial pathogens postulated to be involved in atherosclerosis. A frequent single nucleotide polymorphism (SNP) for the TLR-2 gene, resulting in a non-functional receptor, has been described. By genotyping two independent groups of patients receiving PTCA, followed by stent implantation in one group, we found a significantly enhanced frequency of the TLR-2 Arg753Gln SNP in patients with restenosis as compared to those without restenosis (PTCA: 7.21 versus 2.45%, P = 0.014; PTCA/stent: 6.86 versus 1.53%, P = 0.013). In contrast, a common TLR-4 SNP was similarly distributed among the patient groups investigated. We furthermore compared the frequency of both SNPs in the patients with an age-matched group of individuals without atherosclerosis and found a trend towards a lower frequency of the TLR-4 SNP in the atherosclerotic group (PTCA: 5.58; PTCA/stent: 3.85 versus 7.14%). We conclude that in restenosis a functional TLR-2 is protective and potentially involved in a reaction pattern preventing restenosis. Screening for the TLR-2 Arg753Gln SNP may be of importance for stratifying a patient's risk and for preventive and therapeutic measures.
J Mol Med (Berl) 2005 Jun
PMID:A frequent toll-like receptor (TLR)-2 polymorphism is a risk factor for coronary restenosis. 1587 51

The presence of t(4;14)(p16.3;q32.3) in multiple myeloma cells results in dysregulated expression of the fibroblast growth factor receptor 3 (FGFR3). FGFR3 acts as an oncogene to promote multiple myeloma cell proliferation and antiapoptosis. These encourage the clinical development of FGFR3-specific inhibitors. Three short hairpin RNAs (shRNA) targeting different sites of FGFR3 were selected and subsequently transfected into KMS-11, OPM-2, and NCI-H929 human myeloma cell lines, all of which are characterized by t(4;14) and FGFR3 over expression. The combination of these three shRNAs can effectively inhibit FGFR3 expression in all three cell lines. Sequential immunocytochemistry/fluorescence in situ hybridization was employed to validate that the shRNAs specifically inhibited FGFR3 expression in OPM-2 cells. Decreased expression of B-cell chronic lymphocytic leukemia/lymphoma 2 (BCL2) and myeloid cell leukemia sequence 1 (MCL1) proteins and increased staining of Annexin V-positive cells showed that inhibition of FGFR3 induces apoptosis. After confirming down-regulation of FGFR3 by real-time PCR, HU-133 plus 2.0 array was employed to compare the gene expression profile of shRNA-treated sample with that of the control. Besides the down-regulation of FGFR3, expression of the antiapoptotic genes CFLAR, BCL2, MCL1, and some members of NF-kappaB family decreased, whereas expression of the proapoptotic genes CYC, BID, CASP2, and CASP6 increased. Microarray results also revealed changes in genes previously implicated in multiple myeloma pathogenesis (RAS, RAF, IL-6R, and VEGF), as well as others (TLR4, KLF4, and GADD45A) not previously linked to multiple myeloma. Our observations indicate that shRNAs can specifically and effectively inhibit FGFR3 expression. This targeted approach may be worth testing in multiple myeloma patients with t(4;14) and FGFR3 overexpression in the future.
Mol Cancer Ther 2005 May
PMID:Fibroblast growth factor receptor 3 inhibition by short hairpin RNAs leads to apoptosis in multiple myeloma. 1589 43

Positron emission tomographic imaging after administration of the glucose analog fluorine-18 fluorodeoxyglucose ([18F]FDG) may be useful to study neutrophilic inflammation of the lungs. In this study, we sought to determine the specificity of the increase in lung [18F]FDG uptake after intraperitoneal endotoxin (Etx) for neutrophil influx into mouse lungs and to determine the regulation of glucose uptake after Etx by Toll-like receptors (TLRs) and TNF-alpha. Lung tissue radioactivity measurements by imaging were validated against counts in a gamma well counter. Glucose uptake was quantified as the [18F]FDG tissue-to-blood radioactivity ratio (TBR) after validating this measure against the "gold standard" measure of glucose uptake, the "net influx rate constant." TBR measurements were made in a control group (no intervention), a group administered Etx, and a group administered Etx plus an additional agent (e.g., vinblastine) or Etx administered to a mutant mouse strain. The glucose uptake measurements were compared with measurements of myeloperoxidase. Increases in TBR after Etx were significantly but not completely eliminated by neutrophil depletion with vinblastine. Increases in TBR after Etx were consistent with signaling via either TLR-4 or TLR-2 (the latter probably secondary to peptidoglycan contaminants in Etx preparation) and were decreased by drug inhibition of TLR-4 but not by inhibition of TNF-alpha. Thus molecular imaging can be used to noninvasively monitor biological effects of Etx on lungs in mice, and changes in lung glucose uptake can be used to monitor effects of anti-inflammatory agents. Such imaging capacity provides a powerful new paradigm for translational "mouse-to-human" pulmonary research.
Am J Physiol Lung Cell Mol Physiol 2005 Nov
PMID:Molecular imaging of lung glucose uptake after endotoxin in mice. 1598 36

The concept that mutations in germ-line encoded pattern recognition receptors with immune activating functions are associated with an increased incidence in Crohn's disease (CD) is gaining acceptance. Whether these mutations have similar or distinct effects on cellular physiology remains obscure. The incidence of three single nucleotide polymorphisms (SNPs) within the Nod2 gene and one functional SNP within both the Tlr4 and Tlr5 gene in a Dutch cohort of 637 patients with inflammatory bowel disease and 127 controls was investigated. The functional consequence of mutant NOD2 and TLR4 was investigated by comparing gene expression profiles after stimulation of monocyte-derived dendritic cells (DCs) from homozygous TLR4- and NOD2-mutant patients with lipopolysaccharides and peptidoglycan, respectively. We observed that the R702W and 1007fs Nod2 alleles and the A299G Tlr4 alleles were significantly more prevalent in patients with CD as compared to healthy controls or patients with ulcerative colitis. The phenotype of TLR4- and NOD2-mutant DCs is distinct, but a large number of genes are up- or down-regulated concordantly. These data provide a concept for the genetic basis of CD; mutations in innate immunity cause similar effects on gene transcription and finally result in comparable clinical disease presentation.
J Mol Med (Berl) 2005 Aug
PMID:Consequence of functional Nod2 and Tlr4 mutations on gene transcription in Crohn's disease patients. 1601 May 82


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