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)

Initial recognition of microbes, as they enter the body, is based on germ line-encoded pattern recognition receptors that selectively bind to essential components of pathogens. This allows the body to respond immediately to the microbial invasion before the development of active immunity. The signal-transducing receptors that trigger the acute inflammatory cascade have been elusive until very recently. On the basis of their genetic similarity to the Toll signaling pathway in Drosophila, mammalian Toll-like receptors (TLRs) have been identified. By now, nine transmembrane proteins in the TLR family have been described. Mammalian TLR4 is the signal-transducing receptor activated by the bacterial lipopolysaccharide. The activation of TLR4 leads to DNA binding of the transcription factor NF-kappaB, resulting in activation of the inflammatory cascade. Activation of other TLRs is likely to have similar consequences. TLR2 mediates the host response to Gram-positive bacteria and yeast. TLR1 and TLR6 may participate in the activation of macrophages by Gram-positive bacteria, whereas TLR9 appears to respond to a specific sequence of bacterial DNA. The TLRs that control the onset of an acute inflammatory response are critical antecedents for the development of adaptive acquired immunity. Genetic and developmental variation in the expression of microbial pattern recognition receptors may affect the individual's predisposition to infections in childhood and may contribute to susceptibility to severe neonatal inflammatory diseases, allergies, and autoimmune diseases.
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PMID:Toll-like receptors as sensors of pathogens. 1151 16

Toll-like receptors (TLRs) are phylogenetically conserved receptors that recognize pathogen associated molecular patterns (PAMPS). We previously generated mice lacking TLR2 and TLR4 and showed the differential role of TLR2 and TLR4 in microbial recognition. TLR4 functions as the transmembrane component of the lipopolysaccharide (LPS) receptor, while TLR2 recognizes peptidoglycan from Gram-positive bacteria and lipoprotein. We also generated mice lacking MyD88, an adaptor involved in IL-1R/TLR signalings. The responses to a variety of bacterial components were completely abrogated in MyD88-deficient cells. However, unlike the signaling mediated by other bacterial components such as lipoprotein and bacterial DNA, activation of NF-kappaB and MAP kinases was induced in response to LPS even in the absence of MyD88, which indicates the existence of a MyD88-independent pathway. We have recently found that the MyD88-independent pathway is involved in LPS-induced maturation of dendritic cells (DCs).
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PMID:The role of Toll-like receptors and MyD88 in innate immune responses. 1152 Oct 59

The Toll family of receptors has been implicated in innate recognition and subsequent activation of defense programs against pathogens such as bacteria and fungi. TLR4, for example, signals the presence of lipopolysaccharide (LPS), a membrane constituent of Gram-negative bacteria. LPS signaling via TLR4 is greatly enhanced by a molecule referred to as MD-2, which is associated with the extracellular domain of TLR4. The TLR4/MD-2 complex, therefore, recognizes LPS. RP105, another member of the Toll family, has a striking similarity to TLR4 in that it is associated with an MD-2-like molecule MD-1. B-cells lacking RP105 are severely impaired in LPS-induced proliferation and antibody production. Studies employing transfectants showed that RP105/MD-1, like MD-2, enhances the LPS signaling via TLR4. RP105/MD-1 thus constitutes an LPS-signaling complex on B-cells. These results suggest that a variety of cell surface molecules regulate LPS recognition/signaling by TLR4.
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PMID:Innate recognition of lipopolysaccharide by Toll-like receptor 4/MD-2 and RP105/MD-1. 1152 Oct 60

The inflammatory response to bacterial infections plays an important role in the detection and elimination of invading micro-organisms. Various components of the bacterial cell wall are capable of activating this pro-inflammatory response. In the case of Gram-negative bacteria, lipopolysaccharide (LPS) is the dominant trigger, although other bacterial factors are also capable of activating this systemic inflammatory response. Recently, Toll-like receptors (TLRs) have been implicated in host responses to bacterial pathogens. Specifically, TLR4 mediates LPS responses while TLR2 plays a broader role in the recognition of a variety of bacteria and bacterial antigens. The experiments in this study were designed to examine the role of Gram-negative cell wall components, other than LPS, and their cellular receptors in the host response to infection using an LPS-deficient mutant of Neisseria meningitidis. Although less potent than the parental strain, we found the LPS-deficient mutant to be a capable inducer of the inflammatory response in a variety of cell types. Moreover, cellular activation by this mutant required expression of CD14 and TLR2.
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PMID:Differential roles of TLR2 and TLR4 in the host response to Gram-negative bacteria: lessons from a lipopolysaccharide-deficient mutant of Neisseria meningitidis. 1152 Oct 65

The synthetic antagonists of lipopolysaccharide (LPS), E5531 and E5564, are analogs of the lipid A portion of LPS that not only lack agonistic activity but also inhibit the biological effects of LPS both in vitro and in vivo. The effects of LPS and these synthetic antagonists have been localized to the recently described Toll-like receptor 4 (TLR4). A recent report indicated that the naturally occurring LPS antagonist Rhodobacter sphaeroides LPS loses its antagonist properties and gains pro-inflammatory qualities in the presence of chlorpromazine and other amphipathic drugs. To determine whether these reported actions occur with our chemically defined LPS antagonists, we examined the effects of chlorpromazine, fluphenazine, trifluoperazine, and lidocaine on the antagonism elicited by RsLPS and E5531 in U373 cells, which produce IL-6 in response to LPS. We also tested the effects of these amphipathic molecules on the LPS-neutralizing activity of RsLPS and E5564 on LPS-induced TNF-alpha release in human whole blood. The results indicate that neither chlorpromazine, fluphenazine, trifluoperazine nor lidocaine alter the activity of E5531 or E5564 in an in vitro cell system or human whole blood. Furthermore, chlorpromazine did not affect the antagonistic activity of RsLPS or E5564 on IL-6 generation by peripheral blood mononuclear cells. Thus, based on these data, our purified synthetic LPS-antagonists do not appear to lose their antagonistic properties and/or become agonists in the presence of amphipathic agents or drugs.
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PMID:Examination of chlorpromazine and other amphipathic drugs on the activity of lipopolysaccharide antagonists, E5564 and E5531. 1152 Oct 69

Calorie restriction (CR) is known to prolong the life span and maintain an active immune function in aged mice, but it is still not known if rodents under CR can respond optimally to bacterial infection. We report here on the influence of CR on the response of peritoneal macrophages to lipopolysaccharide, splenic NF-kappaB and NF-interleukin-6 (IL-6) activities, and mortality in polymicrobial sepsis induced by cecal ligation and puncture (CLP). Macrophages from 6-month-old C57BL/6 mice on a calorie-restricted diet were less responsive to lipopolysaccharide, as evidenced by lower levels of IL-12 and IL-6 protein and mRNA expression. Furthermore, in vitro lipopolysaccharide-stimulated macrophages from mice under CR also expressed decreased lipopolysaccharide receptor CD14 levels as well as Toll-like receptor 2 (TLR2) and TLR4 mRNA levels. In addition, the phagocytic capacity and class II (I-A(b)) expression of macrophages were also found to be significantly lower in mice under CR. Mice under CR died earlier (P < 0.005) after sepsis induced by CLP, which appeared to be a result of increased levels in serum of the proinflammatory cytokines tumor necrosis factor alpha and IL-6 and splenic NF-kappaB and NF-IL-6 activation 4 h after CLP. However, mice under CR survived significantly (P < 0.005) longer than mice fed ad libitum when injected with paraquat, a free radical-inducing agent. These data suggest that young mice under CR may be protected against oxidative stress but may have delayed maturation of macrophage function and increased susceptibility to bacterial infection.
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PMID:Effects of calorie restriction on polymicrobial peritonitis induced by cecum ligation and puncture in young C57BL/6 mice. 1152 18

Despite the tremendous inter-individual variability in the response to inhaled toxins, we simply do not understand why certain people develop disease when challenged with environmental agents and others remain healthy. To address this concern, we investigated whether the toll-4 (TLR4) gene, that 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) in the extracellular domain of the TLR4 receptor are associated with a significantly blunted response to inhaled LPS in 83 humans. Transfection of THP-1 cells demonstrates that the Asp299Gly mutation (but not the Thr399Ile mutation) interrupts TLR4-mediated LPS signaling. 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:Inhaled endotoxin, a risk for airway disease in some people. 1153 62

The recognition of microbial pathogens by the innate immune system involves Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns. Different TLRs recognize different pathogen-associated molecular patterns, with TLR-4 mediating the response to lipopolysaccharide from Gram-negative bacteria. All TLRs have a Toll/IL-1 receptor (TIR) domain, which is responsible for signal transduction. MyD88 is one such protein that contains a TIR domain. It acts as an adapter, being involved in TLR-2, TLR-4 and TLR-9 signalling; however, our understanding of how TLR-4 signals is incomplete. Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TIR-domain-containing protein in the human genome. Mal activates NF-kappaB, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. Mal can form homodimers and can also form heterodimers with MyD88. Activation of NF-kappaB by Mal requires IRAK-2, but not IRAK, whereas MyD88 requires both IRAKs. Mal associates with IRAK-2 by means of its TIR domain. A dominant negative form of Mal inhibits NF-kappaB, which is activated by TLR-4 or lipopolysaccharide, but it does not inhibit NF-kappaB activation by IL-1RI or IL-18R. Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction.
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PMID:Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. 1154 29

Toll-like receptors are type-1 transmembrane receptors involved in microbial recognition. TLR4 has been shown to function as the lipopolysaccharide signaling receptor, while TLR2 recognizes peptidoglycans from Gram-positive bacteria, and lipoproteins. TLR9 is involved in the recognition of bacterial DNA (CpG DNA). Although various microbial cell wall components are recognized by different receptors, all of these responses are abrogated in MyD88-deficient cells. These results show that different TLRs recognize different microbial cell wall components, and that MyD88 is an essential signaling molecule shared among interleukin-1 receptor/Toll family members. However, in LPS signaling MyD88-independent pathway is present in addition to MyD88-dependent pathway.
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PMID:[Bacterial infections and toll-like receptors]. 1155 39

Toll-like receptors (TLRs) are ancient microbial pattern recognition receptors highly conserved from Drosophila to humans. To investigate if subsets of human dendritic cell precursors (pre-DC), including monocytes (pre-DC1), plasmacytoid DC precursors (pre-DC2), and CD11c(+) immature DCs (imDCs) are developed to recognize different microbes or microbial antigens, we studied their TLR expression and responses to microbial antigens. We demonstrate that whereas monocytes preferentially express TLR 1, 2, 4, 5, and 8, plasmacytoid pre-DC strongly express TLR 7 and 9. In accordance with these TLR expression profiles, monocytes respond to the known microbial ligands for TLR2 (peptidoglycan [PGN], lipoteichoic acid) and TLR4 (lipopolysaccharide), by producing tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. In contrast, plasmacytoid pre-DCs only respond to the microbial TLR9-ligand, CpG-ODNs (oligodeoxynucleotides [ODNs] containing unmethylated CpG motifs), by producing IFN-alpha. CD11c(+) imDCs preferentially express TLR 1, 2, and 3 and respond to TLR 2-ligand PGN by producing large amounts of TNF-alpha, and to viral double-stranded RNA-like molecule poly I:C, by producing IFN-alpha and IL-12. The expression of distinct sets of TLRs and the corresponding difference in reactivity to microbial molecules among subsets of pre-DCs and imDCs support the concept that they have developed through distinct evolutionary pathways to recognize different microbial antigens.
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PMID:Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. 1156 Oct 1


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