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PubMed1983

Salmonella typhimurium mutants defective in UDP-D-galactose:lipopolysaccharide alpha 1,6-D-galactosyltransferase. Structural, immunochemical, and enzymologic studies of rfaB mutants.

The biochemical defect in a class of Salmonella typhimurium mutants (rfaB) defective in biosynthesis of the lipopolysaccharide core is described. Structural, immunochemical and enzymologic studies showed that: (i) the core polysaccharide completely lacked the branch alpha 1,6-D-galactosyl residue of the normal lipopolysaccharide as shown by methylation analysis and 1H nmr spectroscopy; (ii) the mutant lipopolysaccharides acted as acceptors for transfer of D-galactose from UDP-D-galactose into alpha 1,6 linkage to the proximal D-glucosyl residue of the core in a reaction catalyzed by an enzyme activity present in extracts from rfaB+ cells; (iii) the UDP-D-galactose:(glucosyl)lipopolysaccharide alpha 1,6-D-galactosyltransferase activity was absent from extracts of rfaB cells.

Carbohydrate Sequence↗

PubMed1996

[Antigenic activity of Burkholderia solanacearum lipopolysaccharides].

The interaction of the antiserum against Burkholderia solanacearum ICMP 8110 cells with lipopolysaccharides from 19 strains of B. solanacearum differing in O-specific polysaccharide structure has been studied using ELISA. No correlation was found between the O-specific polysaccharide structure and serological activity of the lipopolysaccharide. Most of the lipopolysaccharides isolated from B. solanacearum strains (except for 4157, 767 and 7942) displayed cross-reactivity with the tested antiserum. These data indicate that the strain under study pertains to the same serogroup. It cannot be excluded that some nonidentified components in the O-specific polysaccharide structure are responsible for the serological activity of the lipopolysaccharide.

Burkholderia↗

PubMed2006

A CD14 domain with lipopolysaccharide-binding and -neutralizing activity.

The interaction of lipopolysaccharide with CD14 plays a key role in signaling that activates an early defense against pathogens but also contributes to the development of sepsis and septic shock. Here we have mapped the entire 356-amino-acid protein with synthetic 20-amino-acid peptides and have identified a new lipopolysaccharide-binding domain with a strong LPS-neutralizing activity. Moreover, analysis of the structure-activity relationship of this peptide, which corresponds to amino acids 81-100 of human CD14, revealed that leucines 87, 91, and 94 are essential for these activities. The functional relevance of these residues was confirmed by cellular expression of mutant CD14 proteins that are no longer able to bind LPS. Furthermore, the peptide provided a basis for the generation of highly soluble analogues with stronger lipopolysaccharide-neutralizing activity.

Binding Sites↗

PubMed2004

Anti-endotoxin agents. 1. Development of a fluorescent probe displacement method optimized for the rapid identification of lipopolysaccharide-binding agents.

Lipopolysaccharides (LPS), otherwise termed 'endotoxins', are outer-membrane constituents of Gram-negative bacteria. Lipopolysaccharides play a key role in the pathogenesis of 'Septic Shock', a major cause of mortality in the critically ill patient. Therapeutic options aimed at limiting downstream systemic inflammatory processes by targeting lipopolysaccharide do not exist at the present time. We have defined the pharmacophore necessary for small molecules to specifically bind and neutralize LPS, and have shown using animal models of sepsis that the sequestration of circulatory LPS by small molecules is a therapeutically viable strategy. Assays reported previously in the literature do not lend themselves well to the rapid screening of large numbers of structurally diverse compounds. In this report, we describe a highly sensitive and robust fluorescent displacement assay using BODIPY TR cadaverine (BC), which binds specifically to the toxic center of LPS, lipid A, and is competitively displaced by compounds displaying an affinity for lipid A. The assay clearly discriminates subtle differences in the binding of polymyxin B, and its nonapeptide derivative, with LPS. The spectral properties of the BODIPY fluorophore are ideally suited for screening diverse structural classes of compounds, including those with conjugated aromatic groups, or with chromophores in the 260-500 nm range. The fluorescent probe: LPS complex is stable under physiologically relevant salt concentrations, resulting in the rapid rejection of spurious binders interacting via non-specific electrostatic interactions, and, therefore, in greatly improved dispersion of ED(50)values.

Acute-Phase Proteins↗

PubMed1993

Lipopolysaccharide (LPS) binding in subpopulations of mouse peritoneal macrophages.

Lipopolysaccharide-binding sites of mouse peritoneal macrophages were demonstrated by means of immunogold technique. Resident peritoneal macrophages identified by peroxidatic activity in the nuclear envelope and in the rough endoplasmic reticulum show moderate and constant specific binding of bacterial lipopolysaccharide from E. coli (026:B6) to cell surface structures. Monocyte-derived macrophages with peroxidatic activity in cytoplasmic granules are characterized by a broad binding pattern. A high percentage of monocyte-derived macrophages bind large amounts of LPS-gold particles whereas some others bind only less lipopolysaccharide. This is a further hint for the existence of monocyte subpopulations. The different binding patterns of LPS after fixation and the inhibitor-ability of this binding supports the hypothesis that LPS binding is at least partly receptor-mediated.

Animals↗

PubMed1993

Regulation of cytokine mRNA expression in lipopolysaccharide-stimulated human macrophages.

One of the responses of the human macrophage to lipopolysaccharide (LPS) is the production of a number of cytokines. The regulation of these cytokines is still not clearly understood. To study this regulation, mRNA levels of interleukin 1 alpha (IL-1 alpha), IL-1 beta, tumor necrosis factor alpha (TNF-alpha), IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-8/neutrophil chemotactic factor were determined in 10-day-old differentiated macrophages following stimulation with a low dose of LPS (0.001 to 10 ng/mL) with use of the polymerase chain reaction. Increased levels of mRNA for IL-8 were detectable after exposure to a very low dose of LPS (0.001 ng/mL) and levels of IL-1 beta and TNF-alpha were detectable only after stimulation with doses of 0.01 ng/mL. The mRNA for IL-8 was detected 30 minutes after the addition of LPS, while those for IL-1 beta and TNF-alpha were only measurable at 1 hour. The mRNAs for IL-1 alpha, IL-6, and GM-CSF were detectable only with a higher dose of lipopolysaccharide and only after a longer exposure time. In addition, the messages for IL-6 and GM-CSF were measurable for a short time, while those of IL-8 and of IL-1 beta were detectable for a longer time. The secretion of TNF-alpha and GM-CSF tightly followed gene activation, and that of IL-6 and IL-8 steadily increased even after the mRNA level of these cytokines returned to baseline. Secretion of IL-1 alpha and IL-1 beta was hardly detected, although their gene activation was obvious. These data indicate that cytokine mRNA levels following lipopolysaccharide stimulation are highly regulated. Individual cytokines show variable patterns of response. These responses are both dose and time dependent and are not necessarily associated with the secretion of protein.

Adult↗

PubMed1997

Constitutive expression of beta-N-acetylhexosaminidase in a microglial cell line: transcriptional modulation by lipopolysaccharide and serum factors.

We investigated the expression of the alpha- and beta-subunits of the lysosomal enzyme beta-N-acetylhexosaminidase in the BV-2 microglial cell line under different culture conditions. Beta-N-acetylhexosaminidase from BV-2 microglia cells was separated into its constituent isoenzymes on diethylaminoethyl (DEAE) cellulose, and its activity was monitored with 4-methylumbelliferyl-beta-N-acetylglucosamine and 4-methylumbelliferyl-beta-N-acetylglucosamine-6-sulphate substrates. Forms corresponding to the mouse isoenzymes A and B were present in the cells incubated in serum-supplemented medium as well as in serum-free medium. Lipopolysaccharide, a well-known activator of microglia in vitro, added to the BV-2 cells in serum-supplemented medium induced a decrease in the specific enzymatic activity determined with the 4-methylumbelliferyl-beta-N-acetylglucosamine substrate. Lipopolysaccharide had no effect on hexosaminidase isoenzyme pattern of BV-2 cells in serum-supplemented medium. The level of alpha-subunit mRNA was increased and the level of beta-subunit mRNA was decreased in BV-2 cells incubated in serum-supplemented medium plus lipopolysaccharide. In the cells incubated in a serum-free medium no significant changes in the hexosaminidase-specific activities towards the above substrates were observed. Interestingly, increased expression of alpha- and beta-subunit mRNA was evident in comparison with cultures in serum-supplemented medium. The present results suggest that the BV-2 cell line may be a useful tool to study the possible role of microglia in the metabolism of brain glycolipids.

Animals↗

PubMed1994

Molecular mimicry between GQ1b ganglioside and lipopolysaccharides of Campylobacter jejuni isolated from patients with Fisher's syndrome.

We isolated Campylobacter jejuni from 2 patients with Fisher's syndrome subsequent to enteritis. Crude lipopolysaccharide fractions were extracted from the bacteria and separated by thin-layer chromatography. Monoclonal antibodies to GQ1b ganglioside (GMR13 and 7F5) reacted with both lipopolysaccharide fractions, indicating that the lipopolysaccharides bear the GQ1b epitope. This is the first report of molecular mimicry between neural tissue components and the antecedent infectious agents of Fisher's syndrome.

Antibodies, Monoclonal↗

PubMed1985

Structural investigations on the inner core region of lipopolysaccharides from Salmonella minnesota rough mutants.

The structure of the inner core region (L-glycero-D-mannoheptose/2-keto-3-deoxy-D-mannooctulosonic acid region) of lipopolysaccharides from Salmonella minnesota rough mutants was investigated. Using conventional methods (neutral sugar analysis, Smith degradation and methylation analysis) combined with gas chromatography/mass spectrometry (GC/MS) of higher oligosaccharides (up to tetrasaccharide), the linkages of the core sugars of lipopolysaccharides from S. minnesota rough mutants, strains R4 (Rd2P-), R7 (Rd1P-) and R5 (RcP-) were determined as: (formula see text) with R representing H in R4, L-glycero-D-mannoheptopyranosyl in R7, and D-glucopyranosyl-(1----3)-L-glycero-D-mannoheptopyranosyl in R5, respectively. In addition, it is shown that heterogeneity within the neutral sugar part of these lipopolysaccharides is low.

Carbohydrates↗

PubMed1983

Isotype commitment in the in vivo immune responses. II. Polyclonal plaque-forming cell responses to lipopolysaccharide in the spleen and bone marrow.

Injection of lipopolysaccharide into adult mice results in a rapid increase in the number of splenic IgM-secreting plaque-forming cells (PFC) so that by 60 h they represent roughly 20 times those present in normal mice. Although inhibited for the first two days, IgG3, IgG2b and IgG2a PFC are later selectively stimulated and, by 110 h, they reach numbers that are 100, 40 and 30 times, respectively, those of normal mice. IgG1 PFC are stimulated only marginally and 48 h after the maximal responses of the other IgG subclasses. IgA PFC are selectively inhibited and drop to 20% of normal numbers 4 days after injection. The ability of lipopolysaccharide to selectively stimulate B cells for the production of IgG3, IgG2b and IgG2a was further substantiated by studying athymic mice, and by using adoptive cell transfers that overcome regulatory influences limiting these responses in intact mice. Under these conditions, 16% of all spleen cells are PFC and up to 85% of all Ig-secreting cells are included in those three isotypes. Similar responses are also detected in bone marrow but they occur 24-48 h after the splenic responses, suggesting that bone marrow PFC are not induced in situ. These results demonstrate a selective in vivo isotype commitment in response to lipopolysaccharide that is polyclonal and, therefore, independent of V region specificities.

Animals↗

PubMed1992

Heat shock prevents lipopolysaccharide-induced tumor necrosis factor-alpha synthesis by rat mononuclear phagocytes.

Tumor necrosis factor-alpha (TNF-alpha), a mononuclear phagocyte-derived peptide is known to participate in the pathogenesis of fever. To determine whether a feedback mechanism exists by which elevated temperatures influence TNF-alpha generation, we have examined the effects of heat shock on the in vitro synthesis of TNF-alpha by rat glomeruli, inflammatory peritoneal macrophages and blood monocytes. Preexposure of peritoneal macrophages to elevated temperatures for 20 min decreased the subsequent lipopolysaccharide-induced release of TNF-alpha bioactivity. The mean reductions were 11.9 +/- 5.0%, 86.3 +/- 12.0%, and 95.2 +/- 3.5% after pretreatment at 39, 41 and 43 degrees C, respectively. Reductions, that were transient, were maximum when lipopolysaccharide was added 0-2 h after heat shock. They correlated with the decreased release of immunoreactive TNF-alpha and the decreased expression of both cell-associated TNF-alpha molecule and TNF-alpha mRNA. Heat shock-induced inhibition of TNF-alpha release was independent of variations of prostaglandin synthesis, but was possibly related to the induction of heat-shock proteins since (a) macrophages exposed to heat shock synthesized the major 70- and 90-kDa heat-shock proteins, and (b) chemical inducers of the heat-shock response were also effective inhibitors of TNF-alpha release. The mean reduction of TNF-alpha release after pretreatment at 41 degrees C was found to be identical in glomerular tissue (82.0 +/- 7.5%), but significantly less in blood monocytes (43.9 +/- 10.9%). This supports the hypothesis that a negative-feedback mechanism exists between elevated temperature and lipopolysaccharide-induced TNF-alpha synthesis, and suggests that this regulation is less active in blood monocytes than in tissue macrophages.

Animals↗

PubMed1991

Alcian blue fixation allows silver staining of the isolated polysaccharide component of bacterial lipopolysaccharides in polyacrylamide gels.

The effect of the cationic dye Alcian Blue on the silver staining of bacterial lipopolysaccharide and its polysaccharide and lipid A portions in polyacrylamide gels was investigated. The polysaccharide was only stained when the gel was previously treated with the dye. The polysaccharide moiety was found to be responsible for the lipopolysaccharide staining with silver, whereas the lipid A seemed unimportant. Treatment with Alcian Blue may prove useful to detect hydrophilic components of lipopolysaccharide samples that could not be stained by the usual silver staining procedures.

Alcian Blue↗

PubMed1995

Interferon-alpha primes macrophages for lipopolysaccharide-induced apoptosis.

Apoptosis plays an important role in generating and maintaining an effective immune system. Many pathogens can perturb the homeostasis of the immune system by either inducing or suppressing cell death of immune cells. Using bovine macrophages as a model, we found that interferon-alpha, one of the host's responses to viral infection, can prime macrophages for activation-induced apoptosis. Exposure of bovine bone-marrow-derived macrophages to interferon-alpha and subsequent activation with lipopolysaccharide led to a strong downregulation of the macrophages' nitric oxide production when compared to lipopolysaccharide stimulation alone. We could show that this was due to induction of apoptosis after activation of the cells. Herpesvirus-induced type I interferon also primed bovine macrophages for lipopolysaccharide-induced apoptosis. Our studies describe how in a novel pathway an antiviral immune response could contribute to pathological sequelae of viral diseases.

Animals↗

PubMed1999

Gastric mucosal inflammatory responses to Helicobacter pylori lipopolysaccharide: down-regulation of nitric oxide synthase-2 and caspase-3 by sulglycotide.

We applied the animal model of H. pylori lipopolysaccharide-induced gastritis to assess the effect of antiulcer agent, sulglycotide, on the mucosal inflammatory responses by analyzing the interplay between the activity of a key apoptotic caspase, caspase-3, epithelial cell apoptosis, and the expression of constitutive (cNOS) and inducible (NOS-2) nitric oxide synthase. H. pylori lipopolysaccharide applied intragastrically elicited within 4 days a pattern of mucosal responses resembling that of acute gastritis. This was accompanied by an 11.2-fold increase in epithelial cell apoptosis, a 6.5-fold induction in mucosal expression of NOS-2 and a 2.2-fold decline in cNOS, and a 5.4-fold increase in caspase-3 activity. Treatment with sulglycotide led to a 56.7% reduction in the extent of mucosal inflammatory changes elicited by H. pylori lipopolysaccharide and an 88.3% decrease in the epithelial cells apoptosis. Furthermore, this effect of sulglycotide was associated with a 51% decrease in mucosal expression of caspase-3 activity, a 73.7% decline in NOS-2, and a 64.1% increase in cNOS. The findings suggest that sulglycotide suppresses the H. pylori-induced mucosal inflammatory responses by up-regulating cNOS and interfering with the events propagated by NOS-2 and caspase-3.

Acute Disease↗

PubMed2002

In vitro toxicity and interactions of environmental contaminants (Arochlor 1254 and mercury) and immunomodulatory agents (lipopolysaccharide and cortisol) on thymocytes from lake trout (Salvelinus namaycush).

The immunotoxicity of chemical combinations commonly encountered by the lake trout (Salvelinus namaycush) immune system was the focus of this study. It was hypothesised that combinations of an environmental contaminant (mercuric chloride or Aroclor 1254) and an immunomodulatory agent (bacterial endotoxin or cortisol) might interact to produce a greater toxicity than that of the environmental contaminant alone at concentrations typically encountered in piscine blood and other tissues. Thus lake trout thymocytes were isolated and treated with mercuric chloride or Aroclor 1254 in the presence and absence of cortisol or lipopolysaccharide. Incubations were performed for 6 or 20 h at 4 degrees C or 10 degrees C. Lipopolysaccharide did not affect the toxicity of either contaminant. In contrast, cortisol enhanced the toxicity of both environmental contaminants. Hence, stressors that lead to increased cortisol production, but not lipopolysaccharide directly, may increase the toxicity of mercury and Aroclor 1254 to lake trout thymocytes.

Adjuvants, Immunologic↗

PubMed1988

Structural changes produced in Kupffer cells in the rat liver by injection of lipopolysaccharide.

The fine structure of Kupffer cells has been studied at various times after an intravenous injection of lipopolysaccharide of Salmonella abortus equii. The most prominent effects were: an increase in the number and dimensions of phagocytic vacuoles (often containing ingested LPS and neutrophilic granulocytes); mitochondrial damage, including disintegration of the matrix and cristae; an increase in the amount of dilated, lucent rough endoplasmic reticulum; presence of fat droplets in the cytoplasm. Five days after injection of lipopolysaccharide, the Kupffer cells had resumed their normal ultrastructure. Several minutes after injection of lipopolysaccharide, platelets adhered to the Kupffer and endothelial cells. Between one and six hours, neutrophilic granulocytes accumulated in the liver sinusoids. The resulting obstruction of the hepatic microcirculation most probably affected cellular ultrastructure by ischaemia. At three days, the number of Kupffer cells was doubled, and increased further at later time intervals.

Animals↗

PubMed1983

Protective activities of ribosomal ribonucleic acid and lipopolysaccharide of Pseudomonas aeruginosa: a comparative study.

Ribosomal ribonucleic acid (RNA) and lipopolysaccharide (LPS) from P. aeruginosa were compared with respect to their protective activities in mice against an infection with P. aeruginosa. This study is concentrated on the protective activity of RNA. RNA isolated from purified ribosomes did not contain LPS as determined with the Limulus test. Injection of RNA with the adjuvant dimethyldioctadecylammonium bromide (DDA) protected mice against P. aeruginosa without inducing LPS-specific antibodies. C3H/HeJ mice which are relatively insensitive to the protective activity of LPS could be protected with RNA. The protective activities of RNA and LPS from a mutant strain of P. aeruginosa, PAC 605, containing defective lipopolysaccharide, were compared with the protective activities of RNA and LPS from the parent strain, PAC IR. The protective activity of LPS from PAC 605 was 1000 fold lower than the protective activity of LPS from PAC IR. RNA preparations of both strains induced similar percentages of survival. The protective activity of ribosomal RNA from P. aeruginosa was nonspecific since mice were also protected against a heterologous serotype of P. aeruginosa and against Escherichia coli. RNA from ribosomes of P. aeruginosa, E. coli and the non-lipopolysaccharide containing Saccharomyces cerevisiae had similar protective activities. No protection was obtained with the ribonucleic acid from the E. coli phage MS2. It is concluded that ribosomal RNA has protective activities distinct from those of LPS.

Animals↗

PubMed1975

Chemical structure and biological activity of endotoxins (lipopolysaccharides) and lipid A.

Lipopolysaccharides (endotoxins) of gram-negative bacteria consist of two components with distinct physico-chemical character: a heteropolysaccharide and a covalently linked lipid, termed lipid A. Chemically, lipid A is made up of acylated glucosamine disaccharides, which are interlinked by pyrophosphate bridges. Lipid A represents the toxic center of lipopolysaccharides. In rabbits, lipid A also induces pyrogen tolerance as well as pyrogen cross-tolerance. Fever tolerance can be passively transferred with serum from rabbits immunized with lipid A. The protective power of lipid A antiserum, however, is only expressed in amimals which have been pretreated with lipid A or lipopolysaccharide, indicating that other than humoral factors, perhaps cellular, also participate in endotoxin tolerance. Lipid A antiserum also prevents the local Shwartzman reaction in rabbits. The possible potency of lipid A antiserum to prevent other endotoxin effects such as lethal shock is presently investigated.

Animals↗