Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathogenesis of filarial disease is characterized by acute and chronic inflammation. Inflammatory responses are thought to be generated by either the parasite, the immune response, or opportunistic infection. We show that soluble extracts of the human filarial parasite Brugia malayi can induce potent inflammatory responses, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and nitric oxide (NO) from macrophages. The active component is heat stable, reacts positively in the Limulus amebocyte lysate assay, and can be inhibited by polymyxin B. TNF-alpha, IL-1beta, and NO responses were not induced in macrophages from lipopolysaccharide (LPS)-nonresponsive C3H/HeJ mice. The production of TNF-alpha after chemotherapy of microfilariae was also only detected in LPS-responsive C3H/HeN mice, suggesting that signaling through the Toll-like receptor 4 (TLR4) is necessary for these responses. We also show that CD14 is required for optimal TNF-alpha responses at low concentrations. Together, these results suggest that extracts of B. malayi contain bacterial LPS. Extracts from the rodent filaria, Acanthocheilonema viteae, which is not infected with the endosymbiotic Wolbachia bacteria found in the majority of filarial parasites, failed to induce any inflammatory responses from macrophages, suggesting that the source of bacterial LPS in extracts of B. malayi is the Wolbachia endosymbiont. Wolbachia extracts derived from a mosquito cell line induced similar LPS-dependent TNF-alpha and NO responses from C3H/HeN macrophages, which were eliminated after tetracycline treatment of the bacteria. Thus, Wolbachia LPS may be one of the major mediators of inflammatory pathogenesis in filarial nematode disease.
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PMID:Inflammatory responses induced by the filarial nematode Brugia malayi are mediated by lipopolysaccharide-like activity from endosymbiotic Wolbachia bacteria. 1077 Aug 8

Gingival fibroblasts produce proinflammatory cytokines in response to lipopolysaccharide (LPS) from periodontopathic bacteria. Recently it has become evident that the human homologue of Drosophila Toll can transduce intracellular signaling by LPS stimulation. Toll-like receptors (TLRs) have been identified in myeloid cells; however, their role in nonmyeloid cells such as gingival fibroblasts has not been fully elucidated. Here, we report that human gingival fibroblasts constitutively express TLR2 and TLR4 and that their levels of expression are increased by stimulation with LPS from Porphyromonas gingivalis. Upregulated expression of interleukin-6 gene and protein in fibroblasts stimulated with LPS is inhibited by anti-TLR4 antibody. These findings suggest that TLRs may confer responsiveness to LPS in gingival fibroblasts.
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PMID:Toll-like receptors confer responsiveness to lipopolysaccharide from Porphyromonas gingivalis in human gingival fibroblasts. 1081 37

There is much variability between individuals in the response to inhaled toxins, but it is not known why certain people develop disease when challenged with environmental agents and others remain healthy. To address this, we investigated whether TLR4 (encoding the toll-like receptor-4), which has been shown to affect lipopolysaccharide (LPS) responsiveness in mice, underlies the variability in airway responsiveness to inhaled LPS in humans. Here we show that common, co-segregating missense mutations (Asp299Gly and Thr399Ile) affecting the extracellular domain of the TLR4 receptor are associated with a blunted response to inhaled LPS in humans. Transfection of THP-1 cells demonstrates that the Asp299Gly mutation (but not the Thr399Ile mutation) interrupts TLR4-mediated LPS signalling. Moreover, the wild-type allele of TLR4 rescues the LPS hyporesponsive phenotype in either primary airway epithelial cells or alveolar macrophages obtained from individuals with the TLR4 mutations. Our findings provide the first genetic evidence that common mutations in TLR4 are associated with differences in LPS responsiveness in humans, and demonstrate that gene-sequence changes can alter the ability of the host to respond to environmental stress.
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PMID:TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. 1083 34

Regulation of the phagocyte apoptotic response appears to play a significant role in the pathophysiology of sepsis. In this regard, prior studies have shown that the onset of phagocyte apoptosis, as well as those agents that regulate it at the nidus of infection, differ significantly from those seen in circulation. The aim of this study therefore was to determine if the increase in inducible phagocyte apoptosis and caspase activities seen in the peritoneum during sepsis is due to endotoxin or Fas ligand. To study this, male C3H/HeN (endotoxin-sensitive), C3H/HeJ (endotoxin-tolerant), and C3H/HeJ-FasL(gld) (endotoxin-tolerant/FasL-deficient) mice were subjected to cecal ligation and puncture or sham operation. Twenty-four hours later, phagocytes were collected and cultured with lipopolysaccharide (LPS), then harvested for apoptosis (propidium iodide cell cycle or cell death ELISA analysis), cytokine release (ELISA), and caspase activity (fluorogenic assay) determination. The data indicate that there was a marked increase in apoptosis in LPS-stimulated phagocytes which was associated with a significant increase in caspase 3, 8, and 9 activities but a decrease in caspase 1 activity from C3H/HeN and C3H/HeJ-FasL(gld) septic mice and an increase in caspase 3 and 8 activities in phagocytes from C3H/HeJ septic mice. Furthermore, cells from septic mice, including all three strains, lost their ability to produce IL-1beta and IL-6 in response to LPS stimulation. The inability to completely suppress these changes suggests that neither endotoxin (via signaling through TLR-4 pathway) nor Fas ligand regulates the peritoneal phagocyte apoptotic responses seen during the late phase of polymicrobial sepsis/peritonitis.
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PMID:Neither Fas ligand nor endotoxin is responsible for inducible peritoneal phagocyte apoptosis during sepsis/peritonitis. 1083 64

The susceptibility to infections induced by Gram-negative bacteria is largely determined by innate immune responses to bacteria cell wall lipopolysaccharide (LPS). The stimulation of B cells by LPS enhances their antigen-presenting capacity and is accompanied by B cell proliferation and secretion of large quantities of LPS-neutralizing antibodies. Similar to macrophages and neutrophils, the LPS-induced activation of B cells is dependent on Toll-like receptor (TLR)4. Here, we demonstrate that the responses of B cells to LPS are also regulated by another TLR protein, RP105, which is predominantly expressed on mature B cells in mice and humans. The analysis of mice homozygous for the null mutation in the RP105 gene revealed impaired proliferative and humoral immune responses of RP105-deficient B cells to LPS. Using originally LPS-unresponsive Ba/F3 cells expressing exogenous TLR4 and RP105, we demonstrate the functional cooperation between TLR4 and RP105 in LPS-induced nuclear factor kappaB activation. These data suggest the existence of the TLR4-RP105 signaling module in the LPS-induced B cell activation.
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PMID:The toll-like receptor protein RP105 regulates lipopolysaccharide signaling in B cells. 1088 May 23

The lipopolysaccharide (LPS) secreted by Porphyromonas gingivalis is implicated in the initiation and progression of periodontitis. Human gingival fibroblasts (HGFs) are the major constituent of gingival connective tissue. In this study, we examined the expression of Toll-like receptor 4 (TLR4) on HGFs by flow cytometric analysis, and studied the signal transduction induced by LPS stimulation of HGFs by enzyme-linked immunosorbent assay, Western blotting, and immunoprecipitation. We show that LPS binds to HGFs, and that HGFs express TLR4 and myeloid differentiation primary response gene 88 (MyD88). P. gingivalis LPS-induced interleukin (IL)-1 production in HGFs was inhibited by anti-TLR4 antibody. P. gingivalis LPS treatment of HGFs activated several intracellular proteins including protein tyrosine kinases, and upregulated the expression of IL-1 receptor-associated kinase (IRAK), nuclear factor-kappaB (NF-kappaB), and activating protein-1 (AP-1), and these events were suppressed by anti-TLR4 monoclonal antibody. Our findings suggest that the binding of P. gingivalis LPS to TLR4 on HGFs activates various second messenger systems.
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PMID:Toll-like receptor 4-mediated signal pathway induced by Porphyromonas gingivalis lipopolysaccharide in human gingival fibroblasts. 1089 89

C3H/HeJ mice have an impaired ability to respond to lipopolysaccharide (LPS) due to a mutation in the gene that encodes Toll-like receptor 4 (TLR4). The effect of TLR4 deficiency on host responses to endodontic infections is unknown. In the present study, we compared periapical bone destruction, sepsis, and inflammatory cytokine production in LPS-hyporesponsive C3H/HeJ and wild-type control C3H/HeOuJ mice. The mandibular first molars of both strains were subjected to pulpal exposure and infection with a mixture of four anaerobic pathogens, Prevotella intermedia, Fusobacterium nucleatum, Streptococcus intermedius, and Peptostreptococcus micros. At sacrifice on day 21, TLR4-deficient C3H/HeJ mice had significantly reduced periapical bone destruction compared to wild-type C3H/HeOuJ mice (P < 0.001). The decreased bone destruction in C3H/HeJ correlated with reduced expression of the bone resorptive cytokines interleukin 1alpha (IL-1alpha) (P < 0.01) and IL-1beta (P < 0.05) as well as the proinflammatory cytokine IL-12 (P < 0.05). No significant differences were seen in the levels of gamma interferon, tumor necrosis factor alpha (TNF-alpha), or IL-10 between the two strains. The expression of IL-1alpha, IL-1beta, TNF-alpha, IL-10, and IL-12 were all significantly reduced in vitro in macrophages from both TLR4-deficient C3H/HeJ and C57BL/10ScNCr strains, compared to wild-type controls. Notably, the responses of TLR4-deficient macrophages to both gram-positive and gram-negative bacteria were similarly reduced. Neither C3H/HeJ nor C3H/HeOuJ mice exhibited orofacial abscess development or infection dissemination as determined by splenomegaly or cachexia. We conclude that intact TLR function mediates increased proinflammatory responses and bone destruction in response to mixed anaerobic infections.
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PMID:Toll-like receptor 4-deficient mice have reduced bone destruction following mixed anaerobic infection. 1089 73

In mice (and by inference, in all mammals), a single pathway exists to serve lipopolysaccharide (LPS) signal transduction, and as such, allelic mutations at a single locus entirely abolish responses to LPS in C3H/HeJ and C57BL/10ScCr mice. Positional cloning of this locus, known as Lps, revealed that mutations of the Toll-like receptor 4 gene (Tlr4) are responsible for endotoxin resistance. A quick succession of studies have shown Tlr4 to be the critical transmembrane component of the LPS signal transduction complex. As LPS sensing by Tlr4 depends on physical contact between the two molecules, Tlr4 is a direct interface with the microbial world. Eight other molecules with strong similarity to Tlr4 are presently known in mammals, and taking Tlr4 as a model, all may be guessed to participate in the early detection of invasive pathogens. Acting together, the Toll-like receptors may be assumed to present macrophages with a comprehensive "picture" of the micobial world, and thus comprise the principal sensing molecules utilized by cells of the innate immune system.
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PMID:Positional cloning of Lps, and the general role of toll-like receptors in the innate immune response. 1090 93

Genetic evidence indicating that TOLL-like receptor 4 (Tlr4) is the lipopolysaccharide (LPS) receptor in mice was reported. However, biochemical evidence that murine Tlr4 confers LPS responsiveness has not been convincingly demonstrated. Inducible cyclooxygenase (COX-2) is selectively expressed in LPS-stimulated macrophages in part mediated through the activation of NF kappa B. Thus, we determined whether murine Tlr4 confers LPS responsiveness as evaluated by the activation of NF kappa B and COX-2 expression. Transfection of a murine macrophage-like cell line (RAW264.7) with the constitutively active form (delta Tlr4) of Tlr4 is sufficient to activate NF kappa B and COX-2 expression. However, the truncated form (delta Tlr4(P712H)) of the missense mutant Tlr4(P712H) found in LPS-hyporesponsive mouse strain (C3H/HeJ) inhibits LPS-induced NF kappa B activation and COX-2 expression. The inability of delta Tlr4(P712H) to activate NF kappa B and induce COX-2 expression is rescued by a constitutively active adapter protein myeloid differentiation factor 88 (MyD88), which interacts directly with the cytoplasmic domain of Tlr proteins. Furthermore, MyD88 is co-immunoprecipitated with the wild-type delta Tlr4 but not with the delta Tlr4(P712H) mutant. Together, these results indicate that Tlr4 confers LPS responsiveness in RAW264.7 cells and suggest that hyporesponsiveness of C3H/HeJ mice to LPS is attributed to the disruption of Tlr4-mediated signaling pathways that results from the inability of the mutant Tlr4(P712H) to interact with MyD88.
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PMID:Murine TOLL-like receptor 4 confers lipopolysaccharide responsiveness as determined by activation of NF kappa B and expression of the inducible cyclooxygenase. 1095 94

Insects defend themselves against infectious microorganisms by synthesizing potent antimicrobial peptides. Drosophila has appeared in recent years as a favorable model to study this innate host defense. A genetic analysis of the regulation of the antifungal peptide drosomycin has demonstrated a key role for the transmembrane receptor Toll, which prompted the search for mammalian homologs. Two of these, Toll-like receptor (TLR)2 and TLR4, recently were shown to play a critical role in innate immunity against bacteria. Here we describe six additional Toll-related genes (Toll-3 to Toll-8) in Drosophila in addition to 18-wheeler. Two of these genes, Toll-3 and Toll-4, are expressed at a low level. Toll-6, -7, and -8, on the other hand, are expressed at high levels during embryogenesis and molting, suggesting that, like Toll and 18w, they perform developmental functions. Finally, Toll-5 is expressed only in larvae and adults. By using chimeric constructs, we have tested the capacity of the signaling Toll/IL-1R homology domains of these receptors to activate antimicrobial peptide promoters and found that only Toll and Toll-5 can activate the drosomycin promoter in transfected cells, thus demonstrating specificity at the level of the Toll/IL-1R homology domain. In contrast, none of these constructs activated antibacterial peptide promoters, suggesting that Toll-related receptors are not involved in the regulation of antibacterial peptide expression. This result was independently confirmed by the demonstration that a dominant-negative version of the kinase Pelle can block induction of drosomycin by the cytokine Spaetzle, but does not affect induction of the antibacterial peptide attacin by lipopolysaccharide.
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PMID:Toll-related receptors and the control of antimicrobial peptide expression in Drosophila. 1100 52


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