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)

A major property of monocytes/macrophages is to recognize and to be activated by bacterial wall components such as LPS, through membrane receptors including the key element CD14. We demonstrate that CD14 expression is down-regulated, as judged by flow cytometry analysis, upon incubation of human monocytes with purified cathepsin G (CG), a releasable neutrophil serine proteinase. The progressive decrease of CD14 expression due to increasing concentrations of CG highly correlates (P < 0.0001) with the decreased synthesis of tumor necrosis factor alpha (TNF-alpha) in response to lipopolysaccharide (LPS). This effect is dependent on the enzymatic activity of CG but is not exerted through an activation of monocytes. Immunoblot analysis reveals that CD14 (M(r) = 57,000) is directly cleaved by CG and released into the extracellular medium as a high-M(r) species (M(r) = 54,000). In this context, incubation of monocytes with activated neutrophils leads to a down-regulation of CD14 expression, a process blocked by a serine proteinase inhibitor. These data suggest a paradoxical anti-inflammatory property for CG.
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PMID:Human neutrophil cathepsin G down-regulates LPS-mediated monocyte activation through CD14 proteolysis. 1094 65

We performed a gene expression screen of the entire transcriptome of the major African malaria vector Anopheles gambiae for immune response genes in adult female mosquitoes, which is the developmental stage infected by malaria parasites. Mosquitoes were immune-stimulated for subtractive cloning by treatment with bacterial lipopolysaccharide, a potent and general elicitor of the innate immune response, and by injury. The screen yielded a highly enriched cDNA library in which more than half of the clones were immune responsive. In this paper, we describe 23 immune-regulated genes, including putative protease inhibitors, serine proteases, regulatory molecules, and a number of genes without known relatives. A molecule related to the protease inhibitor alpha-2-macroglobulin responded strongly to malaria parasite infection, but displayed little or no response to bacteria, whereas other genes exhibited the inverse pattern. These results indicate that the insect immune system discriminates between molecular signals specific to infection with bacteria and malaria parasites.
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PMID:Genes identified by an expression screen of the vector mosquito Anopheles gambiae display differential molecular immune response to malaria parasites and bacteria. 1100 29

Nuclear factor-kappaB (NF-kappa B) is a pleiotropic oxidant-sensitive transcription factor that is present in the cytosol in an inactive form complexed to an inhibitory kappaB (I kappa B) monomer. Various stimuli, including ischemia, hypoxia, free radicals, cytokines, and lipopolysaccharide (LPS), activate NF-kappa B by inducing phosphorylation of I kappa B. Phosphorylation of serine residues at positions 32 and 36 is critical for ubiquitination and degradation of I kappa B alpha with consequent migration of NF-kappa B to the nucleus. Although NF-kappa B is thought to contribute to numerous pathophysiologic processes, definitive assessment of its role has been hindered by the inability to achieve specific inhibition in vivo. Pharmacologic inhibitors of NF-kappa B are available, but their utility for in vivo studies is limited by their relative lack of specificity. Targeted ablation of genes encoding NF-kappa B subunits has not been productive in this regard because of fetal lethality in the case of p65 and functional redundancy in the Rel family of proteins. To overcome these limitations, we have created a viable transgenic mouse that expresses a phosphorylation-resistant mutant of I kappa B alpha (I kappa B alpha(S32A,S36A)) under the direction of a cardiac-specific promoter. Several transgenic lines were obtained with copy numbers ranging from one to seven. The mice exhibit normal cardiac morphology and histology. Total myocardial I kappa B alpha protein level is elevated 3.5- to 6.5-fold with a concomitant 50-60% decrease in the level of I kappa B beta. Importantly, expression of I kappa B(S32A,S36A) results in complete abrogation of myocardial NF-kappa B activation in response to tumor necrosis factor- alpha (TNF-alpha) and LPS stimulation. Thus, novel transgenic mice have been created that make it possible to achieve cardiac-specific and selective inhibition of NF-kappa B in vivo. These transgenic mice should be useful in studies of various cardiac pathophysiological phenomena that involve NF-kappa B activation, including ischemic preconditioning, heart failure, septic shock, acute coronary syndromes, cardiac allograft rejection, and apoptosis.
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PMID:Cardiac-specific abrogation of NF- kappa B activation in mice by transdominant expression of a mutant I kappa B alpha. 1113 32

An antigenic similarity between lipopolysaccharide (LPS) and glycosylated pilin of Pseudomonas aeruginosa 1244 was noted. We purified a glycan-containing molecule from proteolytically digested pili and showed it to be composed of three sugars and serine. This glycan competed with pure pili and LPS for reaction with an LPS-specific monoclonal antibody, which also inhibited twitching motility by P. aeruginosa bearing glycosylated pili. One-dimensional NMR analysis of the glycan indicated the sugars to be 5N beta OHC(4)7NfmPse, Xyl, and FucNAc. The complete proton assignments of these sugars as well as the serine residue were determined by COSY and TOCSY. Electrospray ionization mass spectrometry (MS) determined the mass of this molecule to be 771.5. The ROESY NMR spectrum, tandem MS/MS analysis, and methylation analysis provided information on linkage and the sequence of oligosaccharide components. These data indicated that the molecule had the following structure: alpha-5N beta OHC(4)7NFmPse-(2-->4)beta-Xyl-(1-->3)-beta-FucNAc-(1-->3)-beta-Ser.
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PMID:Structural characterization of the Pseudomonas aeruginosa 1244 pilin glycan. 1134 54

The production of nitric oxide by macrophages has been implicated as a host defense mechanism against microbial pathogens and tumor cells. Recent reports have implicated interferon-alpha/beta (IFN-alpha/beta) as an autocrine/paracrine signal critical for the induction of murine iNOS. In this report we have systematically investigated the role of IFN-beta in the induction of iNOS in the murine macrophage cell line, RAW 264.7. First, we demonstrate that IFN-beta expression is highly up-regulated, and is secreted in response to lipopolysaccharide (LPS). Treatment of RAW macrophages with LPS results in a time-dependent phosphorylation of STAT-1 on both tyrosine residue 701 (Tyr-701) and serine residue 727 (Ser-727) that is consistent with the timing of endogenous IFN-beta expression. LPS also induces interferon regulatory factor-1 expression with similar kinetics. We further demonstrate that exogenous IFN-beta accelerates the induction of iNOS by LPS. The acceleration of iNOS induction is observed at the levels of transcription, protein expression, and NO formation. Accordingly, we propose that the cytokine environment of macrophages may determine the rate and magnitude of nitric oxide production, thereby regulating the cytotoxic response to pathogen challenge.
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PMID:Lipopolysaccharide-induced expression of interferon-beta mediates the timing of inducible nitric-oxide synthase induction in RAW 264.7 macrophages. 1160 90

Mast cell chymase plays important roles in inflammation and tissue remodeling. Here we show that mast cell chymase also functions as an enhancer of immunoglobulin production. In the culture of murine spleen cells stimulated with lipopolysaccharide and interleukin-4, purified rat chymase (rat mast cell protease-I; RMCP-I), at physiological concentrations, enhanced immunoglobulin E (IgE) and IgG1 syntheses but not IgG3 synthesis. The enhancement was also evident when spleen cells depleted of T cells and macrophages were employed as responding cells. Enzymatic activity of RMCP-I was required to enhance IgE and IgG1, because two inhibitors for chymotryptic enzymes, chymostatin and Y-40613, a novel chymase inhibitor, suppressed the enhanced immunoglobulin production, and phenylmethylsulphonyl fluoride, an irreversible inhibitor for serine proteases, totally abolished the enhancing effect. Furthermore, a specific inhibitor for Zn2+-dependent metalloproteases, GI 129471, could also completely inhibit the production of IgE and IgG1 that was enhanced by RMCP-I, suggesting that a metalloprotease also played an essential role in the immunoglobulin production. Our results together with others show that proteases from mast cell granules have important function not only in the efferent phase but also in the afferent phase of immune responses.
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PMID:Rat mast cell protease-I enhances immunoglobulin E production by mouse B cells stimulated with interleukin-4. 1172 48

Individuals with Down syndrome (DS) have a high prevalence of periodontal disease, which develops early and progressed rapidly and extensively, in comparison with healthy controls. The severe periodontal disease in individuals with DS has been considered to result from abnormal factors in their host responses. The mechanisms involved in the periodontal inflammatory processes in individuals with DS are not fully understood. Plasminogen activators (PA) are serine proteases that are well known for their part in the initiation of the fibrinolytic cascade leading to the generation of plasmin in periodontal homeostasis, including fibrinolysis and connective tissue remodeling. The PA-plasmin system affects the progression of periodontal disease. In the present study, we examined the effects of the levels of PA activity stimulated with lipopolysaccharide (LPS) in the gingival fibroblasts from donors with DS (DGF). The levels of PA activity without LPS were low in the DGFs, the same as that in the gingival fibroblasts from donors of healthy controls (NDGF). In contrast, the levels of PA activity with LPS in DGFs were significantly higher than that in the NDGFs. These results suggested that PA plays an important role in inducing extensive and rapid inflammation in the periodontal disease in individuals with DS.
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PMID:Enhancement of plasminogen activator activity stimulated by LPS in gingival fibroblasts of individuals with Down syndrome. 1173 41

We have investigated the importance of cell-surface serine- and/or threonine-linked oligosaccharide adhesion molecules synthesized by the Golgi enzyme core 2 beta-1,6-N-acetylglucosaminyltransferase (C2GlcNAcT) in mediating eosinophil trafficking to the lung in studies utilizing C2GlcNAcT-I-deficient mice. The number of bronchoalveolar eosinophils, the number of lung eosinophils, and airway responsiveness to methacholine were not significantly different in C2GlcNAcT-I-deficient compared with wild-type mice sensitized and challenged by inhalation with ovalbumin. C2GlcNAcT-I-deficient mice do not demonstrate defects in neutrophil trafficking to the lung in response to lipopolysaccharide (LPS). In contrast, ragweed-sensitized C2GlcNAcT-I-deficient mice exhibit significantly reduced eosinophil trafficking to the peritoneal cavity in response to ragweed peritoneal challenge. C2GlcNAcT-I-deficient mice also have significantly reduced neutrophil trafficking to the peritoneal cavity in response to LPS challenge. Overall, these studies demonstrate an important role for serine/threonine-linked oligosaccharides synthesized by the Golgi enzyme C2GlcNAcT-I in eosinophil and neutrophil trafficking to the peritoneum but not for eosinophil or neutrophil trafficking to the lung.
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PMID:Core 2 oligosaccharides mediate eosinophil and neutrophil peritoneal but not lung recruitment. 1179 30

A number of inflammatory cytokines and growth factors promote monocyte survival; however, the biochemical events stimulated by these factors are poorly defined. We previously showed that the monocyte survival factor macrophage colony-stimulating factor (M-CSF) activated monocyte survival through a PI 3-kinase-dependent pathway resulting in the phosphorylation of Akt and the suppression of the activation of caspase-3. Because other cytokines and bacterial cell wall products also induce monocyte survival, we hypothesized that these factors may also suppress caspase-3 and caspase-9 activation and activate Akt in human monocytes. To test this hypothesis, we found that interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, lipopolysaccharide (LPS), granulocyte macrophage-colony-stimulating factor (GM-CSF), and IL-18 appeared to suppress DNA fragmentation, caspase-9, and caspase-3 activation in human monocytes. Moreover, these stimuli appeared to induce the serine and threonine phosphorylation of Akt, which was reduced by the PI 3-kinase inhibitor LY294002. Using in vitro kinase assays, M-CSF appeared to induce more Akt activity than did the other survival factors. Treatment of monocytes with either LY294002 or wortmannin resulted in caspase-3 activation in the presence of these survival factors. These results suggest that monocyte survival factors may suppress DNA fragmentation, caspase-9, and caspase-3 activation in a PI 3-kinase-dependent manner, perhaps through the activation of Akt.
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PMID:Monocyte survival factors induce Akt activation and suppress caspase-3. 1180 74

Previous work (P. Castric, F. J. Cassels, and R. W. Carlson, J. Biol. Chem. 276:26479-26485, 2001) has shown the Pseudomonas aeruginosa 1244 pilin glycan to be covalently bound to a serine residue. N-terminal sequencing of pilin fragments produced from endopeptidase treatment and identified by reaction with a glycan-specific monoclonal antibody indicated that the glycan was present between residue 75 and the pilin carboxy terminus. Further sequencing of these peptides revealed that serine residues 75, 81, 84, 105, 106, and 108 were not modified. Conversion of serine 148, but not serine 118, to alanine by site-directed mutagenesis, resulted in loss of the ability to carry out pilin glycosylation when tested in an in vivo system. These results showed the pilin glycan to be attached to residue 148, the carboxy-terminal amino acid. The carboxy-proximal portion of the pilin disulfide loop, which is adjacent to the pilin glycan, was found to be a major linear B-cell epitope, as determined by peptide epitope mapping analysis. Immunization of mice with pure pili produced antibodies that recognized the pilin glycan. These sera also reacted with P. aeruginosa 1244 lipopolysaccharide as measured by Western blotting and enzyme-linked immunosorbent assay.
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PMID:Identification of the Pseudomonas aeruginosa 1244 pilin glycosylation site. 1201 Sep 70


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