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 enhancement of host susceptibility to endotoxin (lipopolysaccharide, LPS) by toxic shock syndrome toxin-1 (TSST-1) is an important mechanism in the pathogenesis of toxic shock syndrome. In these studies, we sought to determine whether an endotoxin-neutralizing monoclonal antibody could be useful in the treatment of toxic shock syndrome. We isolated a murine monoclonal hybridoma (3-H3) which secreted monoclonal antibody (mAb) specific for Escherichia coli 0111:B4 LPS. Spleen cells cocultured with E. coli 0111:B4 LPS demonstrated up to a 60% decrease in mitogenic activity in the presence of 3-H3 mAb, but not control mAb, demonstrating that this antibody neutralized endotoxin in vitro. Rabbits pretreated with 3-H3 mAb or control mAb were injected intradermally with E. coli 0111:B4 LPS. One day later rabbits received E. coli 0111:B4 LPS intravenously to elicit the dermal Shwartzman reaction. Rabbits pretreated with 3-H3 mAb did not develop this reaction (0/6) compared to animals pretreated with control mAb (5/6), demonstrating that this antibody neutralized endotoxin in vivo (P less than 0.05). When this antibody was evaluated in a rabbit model of lethal toxic shock syndrome, rabbits pretreated with antibody demonstrated greater survival (8/14) than saline control animals (1/10) after challenge with TSST-1 and E. coli 0111:B4 LPS (P less than 0.05). Since the suspicion exists that low levels of endogenous LPS may potentiate TSST-1 activity during clinical toxic shock syndrome, we hypothesized that endotoxin-neutralizing antibodies could be useful in the treatment of this lethal disease process.
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PMID:Treatment of toxic shock syndrome with endotoxin-neutralizing antibody. 273 15

The purpose of this study was to determine whether endotoxin could augment toxic shock syndrome toxin 1 (TSST-1)-induced production of interleukin 1 (IL-1) by murine macrophages. Macrophages from C3H/HeJ or C57Bl/6 mice were stimulated with purified TSST-1 alone or in combination with lipopolysaccharide (LPS). A dramatic synergistic thymocyte-proliferative response was induced by supernatants from C57Bl/6 macrophages stimulated with both TSST-1 and LPS. No enhanced response was induced by supernatants from C3H/HeJ macrophages. A portion of the enhanced response induced by C57Bl/6 macrophage supernatants was attributed to synergism between IL-1 and residual TSST-1 in the thymocyte assay. The addition of monoclonal antibody to TSST-1 to the supernatants eliminated the effects of residual TSST-1 in the thymocyte assay and demonstrated a synergistic induction of IL-1. These data (1) show that LPS can enhance macrophage responsiveness to TSST-1; (2) suggest that TSST-1 not only induces IL-1 secretion but also enhances target cell responsiveness to IL-1; and (3) further support the role of IL-1 in the pathogenesis of toxic shock syndrome.
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PMID:Endotoxin enhancement of toxic shock syndrome toxin 1-induced secretion of interleukin 1 by murine macrophages. 278 86

The hypothesis that toxic shock syndrome toxin 1 (TSST-1) exerts its deleterious effects in toxic shock syndrome (TSS) primarily by enhancing the lethality of small amounts of endogenous endotoxin derived from mucosal colonization with gram-negative bacteria was assessed by evaluating two means of inactivating endotoxin in rabbit models of TSS. In both of these models, toxins and TSST-1 are allowed to diffuse constantly from a subcutaneous depot. Immunologic inactivation of endotoxin with antiserum to the core lipopolysaccharide did not change the clinical course or mortality among animals infected with live TSS-associated staphylococci or among animals with a subcutaneous depot of TSST-1. Anti-TSST-1 was successful in preventing disease and death in these models. Pharmacologic inactivation of endotoxin by pretreatment or continuous treatment with polymyxin B did not prevent illness or mortality in the toxin depot model. Endotoxin thus appears not to be an essential mediator in TSS, since TSS-like illness develops and progresses despite inactivation of endotoxin in animal model systems that are faithful both physiologically and clinically to TSS in humans.
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PMID:Endotoxin is not an essential mediator in toxic shock syndrome. 292 39

The lethal effect of staphylococcal toxic shock syndrome toxin 1 (TSST-1) on rabbits and chick embryos is enhanced in the presence of lipopolysaccharide (LPS). In an investigation of the mode of action of TSST-1, its effect-both singly and in combination with LPS-on tissue culture cell lines was examined. Of a variety of cell lines examined for sensitivity to TSST-1 treatment, only primary chick embryo cells were susceptible. At a critical concentration (0.2 microgram/mL), TSST-1 alone caused detachment of the cell monolayer. In contrast, LPS per se had no visible effect on the cells at any concentration tested. TSST-1 in combination with LPS caused monolayer detachment at all concentrations of TSST-1 employed; thus detachment was independent of TSST-1 concentration in the presence of LPS. The ability of TSST-1 to disrupt the monolayer was neutralized in the presence of polyclonal rabbit antiserum to TSST-1. In a time course study over 24 hours, the effect of the toxin on the cells was initially visible by light microscopy after 4-7 hours. Clear differences in cellular morphology between TSST-1 treated monolayers and untreated controls were observed by scanning electron microscopy. Treated cells lost their normal spindle-shaped appearance before detachment.
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PMID:Damaging effect of toxic shock syndrome toxin 1 on chick embryo cells in vitro. 292 45

The pathogenesis of toxic shock syndrome (TSS) remains unknown. On the basis of experimental data, it has been hypothesized that staphylococcal TSS Toxin 1 (TSST-1) may interact synergistically with low levels of endotoxin and give rise to many of the clinical findings. We have demonstrated previously that lipid A, the biologically active component of lipopolysaccharide (LPS), or endotoxin, induces dose-dependent necrosis of isolated rat renal tubular cells (RTCs). In the present studies, the authors investigated whether this injury could be augmented by TSST-1. The viability of RTCs was assessed by vital dye exclusion. Incubation of freshly isolated rat RTCs with either 1 ng/ml of TSST-1 or 0.1 ng/ml LPS or lipid A had minimal cytotoxicity (less than 6%). Exposure of RTCs to 1 ng/ml TSST-1 for 20 minutes, followed by washing, resulted in a significant enhancement of cytotoxicity when RTCs were exposed to 0.1 ng/ml LPS or lipid A. The sensitization of RTCs by TSST-1 to LPS- or lipid-A-induced injury was prevented by methylamine and chloroquine, two inhibitors of receptor-mediated endocytosis (RME). Chelation of extracellular calcium by 2 mM EGTA also blocked the TSST-1-induced sensitization of RTCs to LPS or lipid A. Inhibition of RTC arachidonic acid metabolism by methylprednisolone, indomethacin, ibuprofen, and piriprost significantly inhibited RTC necrosis induced by TSST-1 and LPS or lipid A by 33-62%. Thiourea and deferoxamine, agents which ameliorate oxidant injury, also inhibited this synergistic injury by 34-67%. Thus, TSST-1 enhanced the cytotoxic effects of LPS/lipid A, and the sensitization of RTCs appeared to involve RME or TSST-1. Oxidative metabolism of arachidonic acid and generation of reactive oxygen species appeared to participate in LPS/lipid-A-mediated RTC death.
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PMID:Enhancement of endotoxin-induced isolated renal tubular cell injury by toxic shock syndrome toxin 1. 307 56

We studied the effect of toxic-shock-syndrome toxin-1 (TSST-1) on production of tumor necrosis factor (TNF) by human monocytes. Adherent mononuclear cells were stimulated with TSST-1 and their supernatants assayed for TNF by using L929 cells in a cytotoxicity assay. TSST-1 stimulated production of TNF over a wide range of concentrations. The cytotoxicity of monocyte supernatants was neutralized by antibody to TNF but not by antibody to interleukin-1 or by normal rabbit serum. TSST-1 and lipopolysaccharide (LPS) had a synergistic effect on monokine production. Monocytes "primed" with TSST-1 produced more interleukin-1 and TNF in response to LPS than did unprimed cells. Treating monocytes with LPS before TSST-1 and co-incubating the two agents with cells for 24 h also enhanced monokine production under some circumstances. These studies suggest a role for TNF in the pathogenesis of toxic shock syndrome, as a consequence of induction by TSST-1 alone or the synergistic effects of several bacterial products.
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PMID:Production of tumor necrosis factor by human monocytes in response to toxic-shock-syndrome toxin-1. 326 47

Staphylococcus aureus strains associated with toxic shock syndrome produce toxic shock syndrome toxin 1 (TSST1). This toxin has a variety of biological effects, including enhanced lethality in rabbits in the presence of sublethal amounts of lipopolysaccharide (LPS). Because chicken embryos are highly susceptible to LPS, the synergistic effect of TSST1 and LPS was examined in this system. Although TSST1 per se had no effect on chicken embryos, it potentiated the lethal effect of LPS. The 50% lethal dose of LPS was greatly reduced in the presence of up to 10 micrograms of TSST1 per ml. However, at high doses of TSST1 (greater than 100 micrograms/ml), no enhanced lethality was observed. The lowest dose of TSST1 tested which potentiated lethality was 10 ng/ml.
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PMID:Effect of toxic shock syndrome toxin 1 on chicken embryos. 397 49

Strains of Staphylococcus aureus associated with toxic shock syndrome produce toxic shock syndrome toxin 1 (TSST 1), which is lethal to conventional rabbits and acts synergistically with gram-negative lipopolysaccharide. The lethal effect of TSST 1 was examined in specific-pathogen-free rabbits on the basis that these rabbits, being less colonized by gram-negative bacteria, would be less susceptible than conventional animals. Although there was no significant difference in mortality between specific-pathogen-free and conventional rabbits in response to 100 micrograms of TSST 1, there was a difference in response between Dutch belted rabbits and New Zealand white rabbits. Both specific-pathogen-free and conventional New Zealand white rabbits were more susceptible to TSST 1 than the Dutch belted strain. Pretreatment of conventional New Zealand white rabbits with polymyxin B neutralized the lethal effect of TSST 1.
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PMID:Toxicity of staphylococcal toxic shock syndrome toxin 1 in rabbits. 650 Jun 91

The mechanism underlying the differentiation of CD4+ T cells into functionally distinct subsets (Th1 and Th2) is incompletely understood, and hitherto unidentified cytokines may be required for the functional maturation of these cells. Here we report the cloning of a recently identified IFN-gamma-inducing factor (IGIF) that augments natural killer (NK) activity in spleen cells. The gene encodes a precursor protein of 192 amino acids and a mature protein of 157 amino acids, which have no obvious similarities to any peptide in the databases. Messenger RNAs for IGIF and interleukin-12 (IL-12) are readily detected in Kupffer cells and activated macrophages. Recombinant IGIF induces IFN-gamma more potently than does IL-12, apparently through a separate pathway. Administration of anti-IGIF antibodies prevents liver damage in mice inoculated with Propionibacterium acnes and challenged with lipopolysaccharide, which induces toxic shock. IGIF may be involved in the development of Th1 cells and also in mechanisms of tissue injury in inflammatory reactions.
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PMID:Cloning of a new cytokine that induces IFN-gamma production by T cells. 862 93

L-selectin, a cell surface adhesion molecule that is expressed by most leukocytes, mediates leukocyte rolling along vascular endothelium at sites of inflammation. The contribution of L-selectin to leukocyte migration in models of chronic inflammation was assessed by using mice that lack cell surface L-selectin expression. Significant inhibition of neutrophil (56-62%), lymphocyte (70-75%), and monocyte (72-78%) migration into an inflamed peritoneum was observed 24 and 48 h after administration of thioglycollate, an inflammatory stimulus. L-selectin-deficient mice were also significantly impaired in delayed-type hypersensitivity reactions. Footpad swelling in response to sheep red blood cell challenge was reduced 75% in L-selectin-deficient mice compared with wild-type mice. Ear swelling in a model of contact hypersensitivity induced by oxazolone challenge was also reduced by 69% compared to wild-type mice. Consistent with L-selectin-mediating leukocyte migration into diverse vascular beds during inflammation, L-selectin-deficient mice were significantly resistant to death resulting from lipopolysaccharide (LPS)-induced toxic shock. LPS administration resulted in a 90% mortality rate in control mice after 24 h, while there was a 90% survival rate in L-selectin-deficient mice. These results demonstrate that L-selectin plays a prominent role in leukocyte homing to nonlymphoid tissues during inflammation and that blocking this process can be beneficial during pathological inflammatory responses.
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PMID:L-selectin-deficient mice have impaired leukocyte recruitment into inflammatory sites. 753 45


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