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

The innate immune system evolved to recognize conserved microbial products, termed pathogen-associated molecular patterns (PAMPs), which are invariant among diverse groups of microorganisms. PAMPs are recognized by a set of germ-line encoded pattern recognition receptors (PRRs). Among the best characterized PAMPs are bacterial lipopolysaccharide (LPS), peptidoglycan (PGN), mannans, and other constituents of bacterial and fungal cell walls, as well as bacterial DNA. Recognition of bacterial DNA is the most enigmatic of these, as it depends on a particular sequence motif, called the CpG motif, in which an unmethylated CpG present in a particular sequence context accounts for a potent immunostimulatory activity of CpG DNA. Receptor(s) of the innate immune system that mediate recognition of CpG DNA are currently unknown. Here, we report that recognition of CpG DNA requires MyD88, an adaptor protein involved in signal transduction by the Toll-like receptors (TLRs), essential components of innate immune recognition in both Drosophila and mammals [1,2]. Signaling induced by CpG DNA was found to be unaffected in cells deficient in TLR2 or TLR4, suggesting that some other member of the Toll family mediates recognition of bacterial DNA.
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PMID:Recognition of CpG DNA is mediated by signaling pathways dependent on the adaptor protein MyD88. 1099 97

ER-112022 is a novel acyclic synthetic lipid A analog that contains six symmetrically organized fatty acids on a noncarbohydrate backbone. Chinese hamster ovary (CHO)-K1 fibroblasts and U373 human astrocytoma cells do not respond to lipopolysaccharide (LPS) in the absence of CD14. In contrast, exposure to ER-112022 effectively induced activation of CHO and U373 cells under serum-free conditions. Expression of CD14 was not necessary for cells to respond to ER-112022, although the presence of soluble CD14 enhanced the sensitivity of the response. Several lines of evidence suggested that ER-112022 stimulates cells via the LPS signal transduction pathway. First, the diglucosamine-based LPS antagonists E5564 and E5531 blocked ER-112022-induced stimulation of CHO-K1, U373, and RAW264.7 cells. Second, ER-112022 was unable to activate C3H/HeJ mouse peritoneal macrophages, containing a mutation in Toll-like receptor (TLR) 4, as well as HEK293 cells, an epithelial cell line that does not express TLR4. Third, ER-112022 activated NF-kappaB in HEK293 cells transfected with TLR4/MD-2. Finally, tumor necrosis factor release from primary human monocytes exposed to ER-112022 was blocked by TLR4 antibodies but not by TLR2 antibodies. Our results suggest that ER-112022 and the family of lipid A-like LPS antagonists can functionally associate with TLR4 in the absence of CD14. Synthetic molecules like ER-112022 may prove to be valuable tools to characterize elements in the LPS receptor complex, as well as to activate or inhibit the TLR4 signaling pathway for therapeutic purposes.
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PMID:A novel synthetic acyclic lipid A-like agonist activates cells via the lipopolysaccharide/toll-like receptor 4 signaling pathway. 1103 43

The Toll signalling pathway, which is required for establishment of dorsoventral polarity in Drosophila embryos, plays an important role in the response to microbial infections. Recently, Toll-like receptors (TLRs) have also been identified in mammals. TLR4 has been shown to function as the transmembrane component of the lipopolysaccharide receptor, while TLR2 recognizes peptidoglycans from Gram-positive bacteria, lipoproteins and yeast. 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 signalling molecule shared among interleukin-1 receptor/Toll family members.
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PMID:Toll-like receptors: lessons from knockout mice. 1104 73

The pro-inflammatory cytokine interleukin-1 (IL-1) signals via the Type-I IL-1 receptor (IL-1RI), inducing an increase in the expression of many genes with roles in immunity and inflammation. The signalling pathways involve two adapter proteins, MyD88 and Tollip, which via two IL-1 receptor-associated kinases (IRAK and IRAK-2) activate transcription factors such as nuclear factor-kappa B and protein kinases such as p38 mitogen-activated protein kinase. A role for the low-molecular-mass G-proteins Rac, Ras and Rap in these processes has also been indicated. IL-1RI is the founder of a diverse superfamily of receptors, which all share a cytosolic domain, termed the Toll/IL-1 receptor (TIR) domain. The superfamily can be divided broadly into three subgroups. The first of these is most similar to IL-1RI and includes the receptor for IL-18 and the Th2 cell regulator T1/ST2. The second subgroup is most similar to the Drosophila melanagaster protein Toll and includes Toll-like receptor 2 (TLR2), which is required for host defence against Gram-positive bacteria and fungi, and TLR4, which is required for lipopolysaccharide responsiveness, and thus is involved in host defence against Gram-negative bacteria. There are also a number of TLRs in plants and insects, all involved in host defence. The third subgroup contains non-receptor proteins which possess a TIR domain and are cytosolic. MyD88 is a member, and it presumably complexes with IL-1RI via a TIR-TIR interaction. The other two members are proteins encoded by the vaccinia virus, A46R and A52R, which block TIR-dependent signalling. This receptor superfamily therefore appears to play a central role in inflammation and host defence against infection, pointing to the TIR domain as a critical molecular player in the innate immune response.
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PMID:The Toll/interleukin-1 receptor domain: a molecular switch for inflammation and host defence. 1104 74

Toll-like receptor (TLR) 2 and TLR4 are members of the interleukin-1 receptor (IL-1R) family and transduce similar signals as IL-1R in response to bacteria and bacterial components. In this study, we investigated the regulation of their gene expression in murine tissues, especially in the liver and hepatocytes. When mice were administered lipopolysaccharide (LPS), TLR2 mRNA was upregulated in the brain, heart, lung, liver, and kidney. In contrast, it was downregulated in the spleen. TLR4 mRNA was decreased in the brain. In the heart and lung, it increased, and it was not affected in the liver, kidney, and spleen. TLR mRNA was further analyzed in the liver and hepatocytes. Like LPS treatment, administration of IL-1, IL-6, or tumor necrosis factor (TNF) upregulated TLR2 mRNA. However, none of them affected the TLR4 mRNA level. In primary cultured hepatocytes, TLR2 mRNA was upregulated by LPS, IL-1, or TNF but not by IL-6 or dexamethasone. None of them affected TLR4 mRNA expression. Similar responses were observed in the murine hepatoma cell line Hepa 1-6. These results suggest that in infection with gram-negative bacteria, LPS and proinflammatory cytokines differentially regulate gene expression of TLR2 and TLR4 in murine hepatocytes, which may lead to pathologic and host defense reactions in the liver.
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PMID:Endotoxin and cytokine regulation of toll-like receptor (TLR) 2 and TLR4 gene expression in murine liver and hepatocytes. 1105 80

Meningococcal disease severity correlates with circulating concentrations of lipopolysaccharide (LPS) and proinflammatory cytokines. Disruption of the lpxA gene of Neisseria meningitidis generated a viable strain that was deficient of detectable LPS. The potency of wild-type N. meningitidis to elicit tumor necrosis factor (TNF)-alpha production by human monocyte-derived macrophages was approximately 10-fold greater than that of the lpxA mutant. Killed wild-type N. meningitidis and its soluble products induced interleukin (IL)-8 and TNF-alpha secretion by transfected HeLa cells expressing Toll-like receptor (TLR) 4/MD2, but the lpxA mutant was inactive via this pathway. In contrast, both strains induced IL-8 promoter activity in TLR2-transfected HeLa cells. These data provide evidence that N. meningitidis contains components other than LPS that can elicit biological responses via pathways that are independent of the TLR4/MD2 receptor system, and TLR2 is one of these alternate pathways. These findings have implications for future therapeutic strategies against meningococcal disease on the basis of the blockade of TLRs and the modulation of LPS activity.
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PMID:A lipopolysaccharide-deficient mutant of Neisseria meningitidis elicits attenuated cytokine release by human macrophages and signals via toll-like receptor (TLR) 2 but not via TLR4/MD2. 1107 7

A search for cellular binding proteins for peptidoglycan (PGN), a CD14- and TLR2-dependent macrophage activator from Gram-positive bacteria, using PGN-affinity chromatography and N-terminal micro-sequencing, revealed that tubulin was a major PGN-binding protein in mouse macrophages. Tubulin also co-eluted with PGN from anti-PGN vancomycin affinity column and bound to PGN coupled to agarose. Tubulin-PGN binding was preferential under the conditions that promote tubulin polymerization, required macromolecular PGN, was competitively inhibited by soluble PGN and tubulin, did not require microtubule-associated proteins, and had an affinity of 100-150 nM. By contrast, binding of tubulin to lipopolysaccharide (LPS) had 2-3 times lower affinity, faster kinetics of binding, and showed positive cooperativity. PGN enhanced tubulin polymerization in the presence of 4 M glycerol, but in the absence of glycerol, both PGN and LPS decreased microtubule polymerization. These results indicate that tubulin is a major PGN-binding protein and that PGN modulates tubulin polymerization.
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PMID:Bacterial peptidoglycan binds to tubulin. 1107 54

Toll-like receptors (TLRs) and the interleukin-1 receptor superfamily (IL-1Rs) are integral to both innate and adaptive immunity for host defence. These receptors share a conserved cytoplasmic domain, known as the TIR domain. A single-point mutation in the TIR domain of murine TLR4 (Pro712His, the Lps(d) mutation) abolishes the host immune response to lipopolysaccharide (LPS), and mutation of the equivalent residue in TLR2, Pro681His, disrupts signal transduction in response to stimulation by yeast and gram-positive bacteria. Here we report the crystal structures of the TIR domains of human TLR1 and TLR2 and of the Pro681His mutant of TLR2. The structures have a large conserved surface patch that also contains the site of the Lps(d) mutation. Mutagenesis and functional studies confirm that residues in this surface patch are crucial for receptor signalling. The Lps(d) mutation does not disturb the structure of the TIR domain itself. Instead, structural and functional studies indicate that the conserved surface patch may mediate interactions with the down-stream MyD88 adapter molecule, and that the Lps(d) mutation may abolish receptor signalling by disrupting this recruitment.
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PMID:Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. 1108 18

An analog of 1alpha,25-dihydroxyvitamin D3, 22-oxyacalcitriol (OCT), differentiated human monocytic THP-1 and U937 cells to express membrane CD14 and rendered the cells responsive to bacterial cell surface components. Both THP-1 and U937 cells expressed Toll-like receptor 4 (TLR4) on the cell surface and TLR4 mRNA in the cells, irrespective of OCT treatment. In contrast, OCT-treated U937 cells scarcely expressed TLR2 mRNA, while OCT-treated THP-1 cells expressed this transcript. Muramyldipeptide (MDP) by itself exhibited only a weak ability to induce secretion of inflammatory cytokines such as interleukin-8 (IL-8) in the OCT-differentiated THP-1 cells but showed marked synergistic effects with Salmonella lipopolysaccharide (LPS) or lipoteichoic acid (LTA) from Staphylococcus aureus, both of which exhibited strong activities. Combinatory stimulation with LPS plus LTA did not show a synergistic effect on OCT-differentiated THP-1 cells. Similar results were observed in OCT-differentiated U937 cells, although combination experiments were carried out only with MDP plus LPS. Anti-CD14 monoclonal antibody (MAb) MY4, anti-TLR4 MAb HTA125, and the synthetic lipid A precursor LA-14-PP almost completely inhibited the IL-8-inducing activities of LTA as well as LPS on OCT-treated THP-1 cells, but these treatments increased MDP activity. OCT-treated THP-1 cells primed with MDP exhibited enhanced production of IL-8 upon stimulation with LPS, while the cells primed with LPS showed no change in production upon stimulation with MDP. MDP up-regulated mRNA expression of an adapter molecule to TLRs, MyD88, to an extent similar to that for LPS in OCT-treated THP-1 cells. These findings suggested that LTA as well as LPS activated human monocytic cells in a CD14- and TLR4-dependent manner, whereas MDP exhibited activity in a CD14-, TLR4-, and probably TLR2-independent manner and exhibited synergistic and priming effects on the cells for cytokine production in response to various bacterial components.
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PMID:Synergistic effect of muramyldipeptide with lipopolysaccharide or lipoteichoic acid to induce inflammatory cytokines in human monocytic cells in culture. 1125 57

The recent isolation of a lipopolysaccharide (LPS)-deficient mutant of Neisseria meningitidis has allowed us to explore the roles of other gram-negative cell wall components in the host response to infection. The experiments in this study were designed to examine the ability of this mutant strain to activate cells. Although it was clearly less potent than the parental strain, we found the LPS-deficient mutant to be a capable inducer of the inflammatory response in monocytic cells, inducing a response similar to that seen with Staphylococcus aureus. Cellular activation by the LPS mutant was related to expression of CD14, a high-affinity receptor for LPS and other microbial products, as well as Toll-like receptor 2, a member of the Toll family of receptors recently implicated in host responses to gram-positive bacteria. In contrast to the parental strain, the synthetic LPS antagonist E5564 did not inhibit the LPS-deficient mutant. We conclude that even in the absence of LPS, the gram-negative cell wall remains a potent inflammatory stimulant, utilizing signaling pathways independent of those involved in LPS signaling.
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PMID:Membrane-associated proteins of a lipopolysaccharide-deficient mutant of Neisseria meningitidis activate the inflammatory response through toll-like receptor 2. 1125 78


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